Benzothiazole cyclobutyl amine derivatives

ABSTRACT

Compounds of formula (I) 
                         
are useful in treating conditions or disorders prevented by or ameliorated by histamine-3 receptor ligands. Also disclosed are pharmaceutical compositions comprising the histamine-3 receptor ligands, methods for using such compounds and compositions, and a process for preparing compounds within the scope of formula (I).

This application claims the benefit of U.S. Provisional PatentApplication No. 60/719,516, filed on Sep. 22, 2005, which is hereinincorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

1. Technical Field

The invention relates to benzothiazole cyclobutyl amine compounds,compositions comprising such compounds, methods for making thecompounds, and methods of treating conditions and disorders using suchcompounds and compositions.

2. Description of Related Technology

Histamine is a well-known modulator of neuronal activity. At least fourtypes of histamine receptors have been reported in the literature,typically referred to as histamine-1, histamine-2, histamine-3, andhistamine-4. The class of histamine receptor known as histamine-3receptors is believed to play a role in neurotransmission in the centralnervous system.

The histamine-3 (H₃) receptor was first characterized pharmacologicallyon histaminergic nerve terminals (Nature, 302:832-837 (1983)), where itregulates the release of neurotransmitters in both the central nervoussystem and peripheral organs, particularly the lungs, cardiovascularsystem and gastrointestinal tract. H₃ receptors are thought to bedisposed presynaptically on histaminergic nerve endings, and also onneurons possessing other activity, such as adrenergic, cholinergic,serotoninergic, and dopaminergic activity. The existence of H₃ receptorshas been confirmed by the development of selective H₃ receptor agonistsand antagonists ((Nature, 327:117-123 (1987); Leurs and Timmerman, ed.“The History of H₃ Receptor: a Target for New Drugs,” Elsevier (1998)).

The activity at the H₃ receptors can be modified or regulated by theadministration of H₃ receptor ligands. The ligands can demonstrateantagonist, inverse agonist, agonist, or partial agonist activity. Forexample, H₃ receptors have been linked to conditions and disordersrelated to memory and cognition processes, neurological processes,cardiovascular function, and regulation of blood sugar, among othersystemic activities. Although various classes of compounds demonstratingH₃ receptor-modulating activity exist, it would be beneficial to provideadditional compounds demonstrating activity at the H₃ receptors that canbe incorporated into pharmaceutical compositions useful for therapeuticmethods.

SUMMARY OF THE INVENTION

The invention is directed to benzothiazole cyclobutyl amines and, moreparticularly, benzothiazole cyclobutyl amine derivatives having acompound of formula (I):

or a pharmaceutically acceptable salt, ester, amide, prodrug, orradiolabelled form thereof, wherein:

m is 0 or 1;

one of R₁ and R₂ is hydrogen, acyl, acyloxy, alkenyl, alkoxy,alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyimino, alkoxysulfonyl,alkyl, alkylcarbonyl, alkylsulfonyl, alkynyl, amido, carboxy, cyano,cycloalkyl, fluoroalkoxy, haloalkoxy, haloalkyl, halogen, hydroxy,hydroxyalkyl, mercapto, nitro, alkylthio, —NR_(A)R_(B),(NR_(A)R_(B))carbonyl, —SO₂N(R_(14a))(R_(14b)), N(R_(14a))SO₂(R_(14b)),a group of the formula —L₂—R₆, or a group of the formula—L_(3a)—R_(6a)—L_(3b)—R_(6b);

the other of R₁ and R₂ is selected from hydrogen, cyano, halogen, alkyl,cycloalkyl, fluoroalkyl, alkoxy, alkoxyalkyl, fluoroalkoxy, alkylthio,—SO₂N(R_(14a)) (R_(14b)), and —N(R_(14a))SO₂(R_(14b));

R_(3a) and R_(3b) are each independently selected from hydrogen, cyano,halogen, alkyl, cycloalkyl, fluoroalkyl, alkoxy, alkoxyalkyl,fluoroalkoxy, alkylthio, —SO₂N(R_(14a))(R_(14b)), and—N(R_(14a))SO₂(R_(14b));

R₄ and R₅ are each independently selected from alkyl, fluoroalkyl,hydroxyalkyl, alkoxyalkyl, and cycloalkyl; or R₄ and R₅ taken togetherwith the nitrogen atom to which each is attached form a non-aromaticring;

R₆ is selected from aryl, heterocycle, and heterocyclealkyl;

R_(6a) is selected from aryl and heterocycle;

R_(6b) is selected from aryl and heterocycle;

L is a bond or alkylene;

L₂ is selected from a bond, —O—, alkylene, —C(═O)—, —S—,—SO₂N(R_(14a))—, —N(R_(14a))SO²⁻—, —C(O)N(R_(14a))—, —N(R_(14a))C(O)—,and —N(R₁₅)—;

L_(3a) and L_(3b) are each independently selected from a bond, —O—,alkylene, —C(═O)—, —S—, —SO₂N(R_(14a))—, —N(R_(14a))SO²⁻—,—C(O)N(R_(14a))—, —N(R_(14a))C(O)—, and —N(R₁₅)—;

R₁₀ is selected from hydrogen, cyano, fluoro, hydroxy, and alkyl;

R_(14a) and R_(14b) are each independently selected at each occurrencefrom hydrogen, alkyl, and cycloalkyl;

R₁₅ is selected from hydrogen, alkyl, acyl, alkoxycarbonyl and(R_(14a))(R_(14b))NC(O)—; and

R_(A) and R_(B) are independently selected from hydrogen, alkyl, acyl,haloalkyl, alkoxycarbonyl, cycloalkyl, and formyl.

Another aspect of the invention relates to pharmaceutical compositionscomprising compounds of the invention. Such compositions can beadministered in accordance with a method of the invention, typically aspart of a therapeutic regimen for treatment or prevention of conditionsand disorders related to H₃ receptor activity.

Yet another aspect of the invention relates to a method of selectivelymodulating H₃ receptor activity. The method is useful for treating, orpreventing conditions and disorders related to H₃ receptor modulation inmammals. More particularly, the method is useful for treating orpreventing conditions and disorders related to memory and cognitionprocesses, neurological processes, cardiovascular function, and bodyweight. Accordingly, the compounds and compositions of the invention areuseful as a medicament for treating or preventing H₃ receptor modulateddisease.

Yet another aspect of the invention relates to radiolabel pharmaceuticalcompositions useful as a radioligand. Radiolabelled forms of compoundsof formula (I) can be provided as compositions of the invention andadministered in accordance with a method of the invention, typically forassessing or diagnosing conditions and disorders related to H₃ receptoractivity, for example in medical imaging. More particularly,positron-emitting isotopes of compounds of the invention may be used formedical imaging in PET (positron emitting tomography), wherein thelocalization of histamine H₃ receptors, and the extent to which thesereceptors are occupied by ligands, can be determined. In this use, thecompounds of the invention possess at least one atom of apositron-emitting isotope selected from ¹¹C, ¹⁸F, ¹⁵O, and ¹³N.Compounds of the invention may also incorporate isotopes that useful forsPECT imaging, for example ¹²³I.

Processes for making compounds of the invention also are contemplated.

The compounds, compositions comprising the compounds, methods for makingthe compounds, methods for treating or preventing conditions anddisorders by administering the compounds, radiolabelled forms of thecompounds, and compositions containing radiolabelled forms of thecompounds are further described herein.

DETAILED DESCRIPTION OF THE INVENTION Definition of Terms

Certain terms as used in the specification are intended to refer to thefollowing definitions, as detailed below.

The term “acyl” as used herein means an alkyl group, as defined herein,appended to the parent molecular moiety through a carbonyl group, asdefined herein. Representative examples of acyl include, but are notlimited to, acetyl, 1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl,and 1-oxopentyl.

The term “acyloxy” as used herein means an acyl group, as definedherein, appended to the parent molecular moiety through an oxygen atom.Representative examples of acyloxy include, but are not limited to,acetyloxy, propionyloxy, and isobutyryloxy.

The term “alkenyl” as used herein means a straight or branched chainhydrocarbon containing from 2 to 10 carbons, and preferably 2, 3, 4, 5,or 6 carbons, and containing at least one carbon-carbon double bond.Representative examples of alkenyl include, but are not limited to,ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl,5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl.

The term “alkoxy” as used herein means an alkyl group, as definedherein, appended to the parent molecular moiety through an oxygen atom.Representative examples of alkoxy include, but are not limited to,methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, andhexyloxy.

The term “alkoxyalkoxy” as used herein means an alkoxy group, as definedherein, appended to the parent molecular moiety through another alkoxygroup, as defined herein. Representative examples of alkoxyalkoxyinclude, but are not limited to, tert-butoxymethoxy, 2-ethoxyethoxy,2-methoxyethoxy, and methoxymethoxy.

The term “alkoxyalkyl” as used herein means an alkoxy group, as definedherein, appended to the parent molecular moiety through an alkyl group,as defined herein. Representative examples of alkoxyalkyl include, butare not limited to, tert-butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl,and methoxymethyl.

The term “alkoxycarbonyl” as used herein means an alkoxy group, asdefined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples ofalkoxycarbonyl include, but are not limited to, methoxycarbonyl,ethoxycarbonyl, and tert-butoxycarbonyl.

The term “alkoxyimino” as used herein means an alkoxy group, as definedherein, appended to the parent molecular moiety through an imino group,as defined herein. Representative examples of alkoxyimino include, butare not limited to, ethoxy(imino)methyl and methoxy(imino)methyl.

The term “alkoxysulfonyl” as used herein means an alkoxy group, asdefined herein, appended to the parent molecular moiety through asulfonyl group, as defined herein. Representative examples ofalkoxysulfonyl include, but are not limited to, methoxysulfonyl,ethoxysulfonyl, and propoxysulfonyl.

The term “alkyl” as used herein means a straight or branched chainhydrocarbon containing from 1 to 10 carbon atoms, and preferably 1, 2,3, 4, 5, or 6 carbons. Representative examples of alkyl include, but arenot limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl,iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl,3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl,n-octyl, n-nonyl, and n-decyl. Each of the carbon atoms of the alkylgroup is substituted with hydrogen or with 0, 1, or 2 substituentsselected from acyl, acyloxy, alkoxy, alkoxyalkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxyimino, alkoxysulfonyl, alkylcarbonyl,alkylsulfonyl, amido, carboxy, cyano, cycloalkyl, fluoroalkoxy, formyl,haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro,oxo, alkylthio, —NR_(A)R_(B), (NR_(A)R_(B))carbonyl, and(NR_(A)R_(B))sulfonyl.

The term “alkylene” means a divalent group derived from a straight orbranched chain hydrocarbon of from 1 to 10 carbon atoms. Representativeexamples of alkylene include, but are not limited to, —CH₂—, —CH(CH₃)—,—C(CH₃)₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, and —CH₂CH(CH₃)CH₂—.

The term “alkylamino” as used herein means an alkyl group, as definedherein, appended to the parent molecular moiety through a NH group.Representative examples of alkylamino include, but are not limited to,methylamino, ethylamino, isopropylamino, and butylamino.

The term “alkylcarbonyl” as used herein means an alkyl group, as definedherein, appended to the parent molecular moiety through a carbonylgroup, as defined herein. Representative examples of alkylcarbonylinclude, but are not limited to, methylcarbonyl, ethylcarbonyl,isopropylcarbonyl, n-propylcarbonyl, and the like.

The term “alkylsulfonyl” as used herein means an alkyl group, as definedherein, appended to the parent molecular moiety through a sulfonylgroup, as defined herein. Representative examples of alkylsulfonylinclude, but are not limited to, methylsulfonyl and ethylsulfonyl.

The term “alkylthio” as used herein, means an alkyl group, as definedherein, appended to the parent molecular moiety through a sulfur atom.Representative examples of alkylthio include, but are not limited,methylthio, ethylthio, tert-butylthio, and hexylthio.

The term “alkynyl” as used herein means a straight or branched chainhydrocarbon group containing from 2 to 10 carbon atoms, and preferably2, 3, 4, or 5 carbons, and containing at least one carbon-carbon triplebond. Representative examples of alkynyl include, but are not limitedto, acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and1-butynyl.

The term “amido” as used herein means an amino, alkylamino, ordialkylamino group appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples of amidoinclude, but are not limited to, aminocarbonyl, methylaminocarbonyl,dimethylaminocarbonyl, and ethylmethylaminocarbonyl.

The term “amino” as used herein means an —NH₂ group.

The term “aryl,” as used herein, means phenyl, a bicyclic aryl, or atricyclic aryl. The bicyclic aryl is attached to the parent molecularmoiety through any carbon atom contained within the bicyclic aryl.Representative examples of the bicyclic aryl include, but are notlimited to, dihydroindenyl, indenyl, naphthyl, dihydronaphthalenyl, andtetrahydronaphthalenyl. The tricyclic aryl is a tricyclic aryl ringsystem such as anthracene or phenanthrene, a bicyclic aryl fused to acycloalkyl, a bicyclic aryl fused to a cycloalkenyl, or a bicyclic arylfused to a phenyl. The tricyclic aryl is attached to the parentmolecular moiety through any carbon atom contained within the tricyclicaryl. Representative examples of tricyclic aryl ring include, but arenot limited to, anthracenyl, phenanthrenyl, azulenyl,dihydroanthracenyl, fluorenyl, and tetrahydrophenanthrenyl.

The carbon atoms of the aryl groups of this invention are substitutedwith hydrogen or are optionally substituted with one or moresubstituents independently selected from acyl, acyloxy, alkenyl, alkoxy,alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyimino, alkoxysulfonyl,alkyl, alkylcarbonyl, alkylsulfonyl, alkynyl, amido, carboxy, cyano,cycloalkyl, fluoroalkoxy, formyl, haloalkoxy, haloalkyl, halogen,hydroxy, hydroxyalkyl, mercapto, nitro, alkylthio, —NR_(A)R_(B),(NR_(A)R_(B))carbonyl, —SO₂N(R_(14a))(R_(14b)), andN(R_(14a))SO₂(R_(14b)). Where the aryl group is a phenyl group, thenumber of substituents is 0, 1, 2, 3, 4, or 5. Where the aryl group is abicyclic aryl, the number of substituents is 0, 1, 2, 3, 4, 5, 6, 7, 8,or 9. Where the aryl group is a tricyclic aryl, the number ofsubstituents is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9.

The term “arylalkyl” as used herein means an aryl group, as definedherein, appended to the parent molecular moiety through an alkyl group,as defined herein. Representative examples of arylalkyl include, but arenot limited to, benzyl, 2-phenylethyl and 3-phenylpropyl.

The term “carbonyl” as used herein means a —C(═O)— group.

The term “carboxy” as used herein means a —CO₂H group, which may beprotected as an ester group —CO₂-alkyl.

The term “cyano” as used herein means a —CN group, attached to theparent molecular moiety through the carbon.

The term “cyanophenyl” as used herein means a —CN group appended to theparent molecular moiety through a phenyl group, including, but notlimited to, 4-cyanophenyl, 3-cyanophenyl, and 2-cyanophenyl.

The term “cycloalkyl” as used herein means a saturated cyclichydrocarbon group containing from 3 to 8 carbons. Examples of cycloalkylinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,and cyclooctyl.

Each of the carbon atoms of the cycloalkyl groups of the invention issubstituted with 0, 1, or 2 substituents selected from acyl, acyloxy,alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyimino,alkoxysulfonyl, alkyl, alkylcarbonyl, alkylsulfonyl, alkynyl, amido,carboxy, cyano, cycloalkyl, fluoroalkoxy, formyl, haloalkoxy, haloalkyl,halogen, hydroxy, hydroxyalkyl, mercapto, nitro, alkylthio,—NR_(A)R_(B), (NR_(A)R_(B))carbonyl, —SO₂N(R_(14a))(R_(14b)), and—N(R_(14a))SO₂(R_(14b)).

The term “cycloalkylcarbonyl” as used herein means a cycloalkyl group,as defined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples ofcycloalkylcarbonyl include, but are not limited to, cyclopropylcarbonyl,cyclopentylcarbonyl, cyclohexylcarbonyl, and cycloheptylcarbonyl.

The term “dialkylamino” as used herein means two independent alkylgroups, as defined herein, appended to the parent molecular moietythrough a nitrogen atom. Representative examples of dialkylaminoinclude, but are not limited to, dimethylamino, diethylamino,ethylmethylamino, and butylmethylamino.

The term “fluoro” as used herein means —F.

The term “fluoroalkyl” as used herein means at least one fluoro group,as defined herein, appended to the parent molecular moiety through analkyl group, as defined herein. Representative examples of fluoroalkylinclude, but are not limited to, fluoromethyl, difluoromethyl,trifluoromethyl, pentafluoroethyl, and 2,2,2-trifluoroethyl.

The term “fluoroalkoxy” as used herein means at least one fluoro group,as defined herein, appended to the parent molecular moiety through analkoxy group, as defined herein. Representative examples of fluoroalkoxyinclude, but are not limited to, fluoromethoxy, difluoromethoxy,trifluoromethoxy, pentafluoroethoxy, heptafluoropropyloxy, and2,2,2-trifluoroethoxy.

The term “formyl” as used herein means a —C(O)H group.

The term “halo” or “halogen” as used herein means Cl, Br, I, or F.

The term “haloalkoxy” as used herein means at least one halogen, asdefined herein, appended to the parent molecular moiety through analkoxy, as defined herein. Representative examples of haloalkoxyinclude, but are not limited to, 2-fluoroethoxy, trifluoromethoxy, andpentafluoroethoxy.

The term “haloalkyl” as used herein means at least one halogen, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of haloalkyl include,but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl,pentafluoroethyl, and 2-chloro-3-fluoropentyl.

The term “heterocycle”, as used herein, refers to aromatic ornon-aromatic cyclic groups that contain at least one heteroatom.Examples of aromatic heterocycles are, for example, heteroaryl groups asfurther defined below. Non-aromatic heterocycles are non-aromatic cyclicgroups that contain at least one heteroatom; examples of non-aromaticheterocyclic groups or non-aromatic heterocycles are further definedbelow. Heterocyclic rings are connected to the parent molecular moietythrough a carbon atom, or alternatively in the case of heterocyclicrings that contain a bivalent nitrogen atom having a free site forattachment, the heterocyclic ring may be connected to the parentmolecular moiety though a nitrogen atom. Additionally, the heterocyclesmay be present as tautomers.

The term “heteroaryl”, as used herein, refers to an aromatic ringcontaining one or more heteroatoms independently selected from nitrogen,oxygen, or sulfur, or a tautomer thereof. Such rings can be monocyclicor bicyclic as further described herein. Heteroaryl rings are connectedto the parent molecular moiety, or to L₂, L_(3a), or L_(3b), wherein L₂,L_(3a), or L_(3b) are defined in formula (I), through a carbon ornitrogen atom.

The terms “monocyclic heteroaryl” or “5- or 6-membered heteroaryl ring”,as used herein, refer to 5- or 6-membered aromatic rings containing 1,2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, orsulfur, or a tautomer thereof. Examples of such rings include, but arenot limited to, a ring wherein one carbon is replaced with an O or Satom; one, two, or three N atoms are arranged in a suitable manner toprovide an aromatic ring; or a ring wherein two carbon atoms in the ringare replaced with one O or S atom and one N atom. Such rings caninclude, but are not limited to, a six-membered aromatic ring whereinone to four of the ring carbon atoms are replaced by nitrogen atoms,five-membered rings containing a sulfur, oxygen, or nitrogen in thering; five-membered rings containing one to four nitrogen atoms; andfive-membered rings containing an oxygen or sulfur and one to threenitrogen atoms. Representative examples of 5- to 6-membered heteroarylrings include, but are not limited to, furyl, imidazolyl, isoxazolyl,isothiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl,pyrimidinyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiadiazolonyl,thiadiazinonyl, oxadiazolyl, oxadiazolonyl, oxadiazinonyl, thiazolyl,thienyl, triazinyl, triazolyl, triazolyl, pyridazinonyl, pyridonyl, andpyrimidinonyl.

The term “bicyclic heteroaryl” or “8- to 12-membered bicyclic heteroarylring”, as used herein, refers to an 8-, 9-, 10-, 11-, or 12-memberedbicyclic aromatic ring containing at least 3 double bonds, and whereinthe atoms of the ring include one or more heteroatoms independentlyselected from oxygen, sulfur, and nitrogen. Representative examples ofbicyclic heteroaryl rings include indolyl, benzothienyl, benzofuranyl,indazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl,benzoisothiazolyl, benzoisoxazolyl, quinolinyl, isoquinolinyl,quinazolinyl, quinoxalinyl, phthalazinyl, pteridinyl, purinyl,naphthyridinyl, cinnolinyl, thieno[2,3-d]imidazole,1,5-dihydro-benzo[b][1,4]diazepin-2-on-yl, and pyrrolopyrimidinyl.

Heteroaryl groups of the invention, whether monocyclic or bicyclic, maybe substituted with hydrogen, or optionally substituted with one or moresubstituents independently selected from acyl, acyloxy, alkenyl, alkoxy,alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyimino, alkoxysulfonyl,alkyl, alkylcarbonyl, alkylsulfonyl, alkynyl, amido, carboxy, cyano,cycloalkyl, fluoroalkoxy, formyl, haloalkoxy, haloalkyl, halogen,hydroxy, hydroxyalkyl, mercapto, nitro, oxo, alkylthio, —NR_(A)R_(B),(NR_(A)R_(B))carbonyl, —SO₂N(R_(14a))(R_(14b)), and—N(R_(14a))SO₂(R_(14b)). Monocyclic heteroaryl or 5- or 6-memberedheteroaryl rings are substituted with 0, 1, 2, 3, 4, or 5 substituents.Bicyclic heteroaryl or 8- to 12-membered bicyclic heteroaryl rings aresubstituted with 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9 substituents.Heteroaryl groups of the present invention may be present as tautomers.

The terms “non-aromatic heterocyclic ring” and “non-aromaticheterocycle”, as used herein, refer to a 4- to 12-membered monocyclic orbicyclic ring containing at least one saturated carbon atom, and alsocontaining one, two, three, four, or five heteroatoms independentlyselected from the group consisting of nitrogen, oxygen, and sulfur.Four- and five-membered rings may have zero or one double bond.Six-membered rings may have zero, one, or two double bonds. Seven- andeight-membered rings may have zero, one, two, or three double bonds. Thenon-aromatic heterocycle groups of the invention can be attached througha carbon atom or a nitrogen atom. The non-aromatic heterocycle groupsmay be present in tautomeric form. Representative examples ofnitrogen-containing heterocycles include, but are not limited to,azepanyl, azetidinyl, aziridinyl, azocanyl, morpholinyl, piperazinyl,piperidinyl, pyrrolidinyl, pyrrolinyl, dihydrothiazolyl,dihydropyridinyl, and thiomorpholinyl. Representative examples ofnon-nitrogen containing non-aromatic heterocycles include, but are notlimited to, dioxanyl, dithianyl, tetrahydrofuryl, dihydropyranyl,tetrahydropyranyl, and [1,3]dioxolanyl.

The non-aromatic heterocycles of the invention substituted withhydrogen, or optionally substituted with 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9substituents independently selected from acyl, acyloxy, alkenyl, alkoxy,alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyimino, alkoxysulfonyl,alkyl, alkylcarbonyl, alkylsulfonyl, alkynyl, amido, carboxy, cyano,cycloalkyl, fluoroalkoxy, formyl, haloalkoxy, haloalkyl, halogen,hydroxy, hydroxyalkyl, mercapto, nitro, oxo, alkylthio, —NR_(A)R_(B),(NR_(A)R_(B))carbonyl, —SO₂N(R_(14a))(R_(14b)), and—N(R_(14a))SO₂(R_(14b)).

Additional examples of heterocycles include, but are not limited to,isoindoline-1,3-dione, (Z)-1H-benzo[e][1,4]diazepin-5(4H)-one,pyrimidine-2,4(1H,3H)-dione, benzo[d]thiazol-2(3H)-one,pyridin-4(1H)-one, imidazolidin-2-one, 1H-imidazol-2(3H)-one,pyridazin-3(2H)-one, tetrahydropyrimidin-2(1H)-one, and1H-benzo[d]imidazol-2(3H)-one.

The term “heterocyclealkyl” as used herein means a heterocycle group, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of heterocyclealkylinclude, but are not limited to, 2-thienylmethyl, 2-thienylethyl,2-furylethyl, and 2-furylmethyl.

The term “hydroxy” as used herein means an —OH group.

The term “hydroxyalkyl” as used herein means at least one hydroxy group,as defined herein, appended to the parent molecular moiety through analkyl group, as defined herein. Representative examples of hydroxyalkylinclude, but are not limited to, hydroxymethyl, 2-hydroxyethyl,2-methyl-2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypentyl, and2-ethyl-4-hydroxyheptyl.

The term “hydroxy-protecting group” means a substituent which protectshydroxyl groups against undesirable reactions during syntheticprocedures. Examples of hydroxy-protecting groups include, but are notlimited to, methoxymethyl, benzyloxymethyl, 2-methoxyethoxymethyl,2-(trimethylsilyl)ethoxymethyl, benzyl, triphenylmethyl,2,2,2-trichloroethyl, t-butyl, trimethylsilyl, t-butyidimethylsilyl,t-butyidiphenylsilyl, methylene acetal, acetonide benzylidene acetal,cyclic ortho esters, methoxymethylene, cyclic carbonates, and cyclicboronates. Hydroxy-protecting groups are appended onto hydroxy groups byreaction of the compound that contains the hydroxy group with a base,such as triethylamine, and a reagent selected from an alkyl halide,alkyl trifilate, trialkylsilyl halide, trialkylsilyl triflate,aryidialkylsilyltriflate, or an alkylchloroformate, CH₂I₂, or adihaloboronate ester, for example with methyliodide, benzyl iodide,triethylsilyltriflate, acetyl chloride, benzylchloride, ordimethylcarbonate. A protecting group also may be appended onto ahydroxy group by reaction of the compound that contains the hydroxygroup with acid and an alkyl acetal.

The term “imino” as defined herein means a —C(═NH)— group.

The term “mercapto” as used herein means a —SH group.

The term “(NR_(A)R_(B))alkyl” as used herein means an —NR_(A)R_(B)group, as defined herein, appended to the parent molecular moietythrough an alkyl group, as defined herein. R_(A) and R_(B) areindependently selected from hydrogen, alkyl, acyl, cycloalkyl, andformyl. Representative examples of (NR_(A)R_(B))alkyl include, but arenot limited to, 2-(methylamino)ethyl, 2-(dimethylamino)ethyl,2-(amino)ethyl, 2-(ethylmethylamino)ethyl, and the like.

The term “(NR_(A)R_(B))carbonyl” as used herein means an —NR_(A)R_(B)group, as defined herein, appended to the parent molecular moietythrough a carbonyl group, as defined herein. Representative examples of(NR_(A)R_(B))carbonyl include, but are not limited to, aminocarbonyl,(methylamino)carbonyl, (dimethylamino)carbonyl,(ethylmethylamino)carbonyl, and the like.

The term “(NR_(A)R_(B))sulfonyl” as used herein means a —NR_(A)R_(B)group, as defined herein, appended to the parent molecular moietythrough a sulfonyl group, as defined herein. Representative examples of(NR_(A)R_(B))sulfonyl include, but are not limited to, aminosulfonyl,(methylamino)sulfonyl, (dimethylamino)sulfonyl and(ethylmethylamino)sulfonyl.

The term “—N(R_(14a))SO₂(R_(14b))” as used herein means an amino groupattached to the parent moiety to which is further appended with anR_(14a) group as defined herein, and a SO₂ group to which is appended an(R_(14b)) group as defined herein. Representative examples of—N(R_(14a))SO₂(R_(14b)) include, but are not limited to,N-methylmethanesulfonamide.

The term “—SO₂N(R_(14a))(R_(14b))” as used herein means aN(R_(14a))(R_(14b)) group attached to a SO₂ group, appended to theparent moiety through the sulfonyl group. Representative examples of—SO₂N(R_(14a))(R_(14b)) include, but are not limited to(dimethylamino)sulfonyl and N-cyclohexyl-N-methylsulfonyl.

The term “nitro” as used herein means a —NO₂ group.

The term “nitrogen protecting group” as used herein means those groupsintended to protect a nitrogen atom against undesirable reactions duringsynthetic procedures. Nitrogen protecting groups comprise carbamates,amides, N-benzyl derivatives, and imine derivatives. Preferred nitrogenprotecting groups are acetyl, benzoyl, benzyl, benzyloxycarbonyl (Cbz),formyl, phenylsulfonyl, pivaloyl, tert-butoxycarbonyl (Boc),tert-butylacetyl, trifluoroacetyl, and triphenylmethyl (trityl).Nitrogen-protecting groups are appended onto primary or secondary aminogroups by reacting the compound that contains the amine group with base,such as triethylamine, and a reagent selected from an alkyl halide, analkyl trifilate, a dialkyl anhydride, for example as represented by analkyl anhydride (alkyl-OC═O)₂O, a diaryl anhydride, for example asrepresented by (aryl-OC═O)₂O, an acyl halide, an alkylchloroformate, oran alkylsulfonylhalide, an arylsulfonylhalide, or halo-CON(alkyl)₂, forexample acetylchloride, benzoylchloride, benzylbromide,benzyloxycarbonylchloride, formylfluoride, phenylsulfonylchloride,pivaloylchloride, (tert-butyl-O—C═O)₂O, trifluoroacetic anhydride, andtriphenylmethylchloride.

The term “oxo” as used herein means (═O).

The term “sulfonyl” as used herein means a —S(O)₂— group.

As used herein, the term “antagonist” encompasses and describescompounds that prevent receptor activation by an H₃ receptor agonistalone, such as histamine, and also encompasses compounds known as“inverse agonists”. Inverse agonists are compounds that not only preventreceptor activation by an H₃ receptor agonist, such as histamine, butalso inhibit intrinsic H₃ receptor activity.

As used herein, the term “radiolabel” refers to a compound of theinvention in which at least one of the atoms is a radioactive atom orradioactive isotope, wherein the radioactive atom or isotopespontaneously emits gamma rays or energetic particles, for example alphaparticles or beta particles, or positrons. Examples of such radioactiveatoms include, but are not limited to, ³H (tritium), ¹⁴C, ¹¹C, ¹⁵O, ¹⁸F,³⁵S, ¹²³I, and ¹²⁵I.

Compounds of the Invention

Compounds of the invention can have the formula (I) as described in theSummary of the Invention

In compounds of formula (I), m is 0 or 1. Preferably, m is 0.

L is a bond or L is alkylene. L is preferably a bond.

One of R₁ and R₂ in a compound of formula (I) is hydrogen, acyl,acyloxy, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl,alkoxyimino, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylsulfonyl,alkynyl, amido, carboxy, cyano, cycloalkyl, fluoroalkoxy, haloalkoxy,haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, alkylthio,—NR_(A)R_(B), (NR_(A)R_(B))carbonyl, —N(R_(A))alkylsulfonyl,(NR_(14a)R_(14b))sulfonyl, or a group of the formula —L₂—R₆ or—L_(3a)—R_(6a)—L_(3b)—R_(6b). The other group represented by R₁ or R₂ ishydrogen, cyano, halogen, alkyl, cycloalkyl, fluoroalkyl, alkoxy,alkoxyalkyl, fluoroalkoxy, alkylthio, SO₂N(R_(14a))(R_(14b)), orN(R_(14a))SO₂(R_(14b)), wherein R_(14a) and R_(14b) are eachindependently hydrogen, alkyl, or cycloalkyl, and more preferably arehydrogen or alkyl, particularly methyl. When R₁ or R₂ is not —L₂—R₆ or—L_(3a)—R_(6a)—L_(3b)—R_(6b), the preferred group is hydrogen.

Preferably, R₁ is —L₂—R₆ or —L_(3a)—R_(6a)—L_(3b)—R_(6b) and R₂ ishydrogen, cyano, halogen, alkyl, cycloalkyl, fluoroalkyl, alkoxy,alkoxyalkyl, and fluoroalkoxy. More preferably, R₁ is —L₂—R₆.

L₂ is selected from a bond, —O—, alkylene, —C(═O)—, —S—,—SO₂N(R_(14a))—, N(R_(14a))SO²⁻—, C(O)N(R_(14a))—, —N(R_(14a))C(O)—, and—N(R₁₅)—. Preferably, L₂ is a bond.

Preferably, R₆ is a heterocycle. Examples of suitable heterocycles forR₆ include, but are not limited to, furyl, imidazolyl, isoxazolyl,isothiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl,pyrimidinyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiadiazolonyl,thiadiazinonyl, oxadiazolyl, oxadiazolonyl, oxadiazinonyl, thiazolyl,thienyl, triazinyl, triazolyl, triazolyl, pyridazinonyl, pyridonyl,pyrimidinonyl, indolyl, benzothienyl, benzofuranyl, indazolyl,benzimidazolyl, benzothiazolyl, benzoxazolyl, benzoisothiazolyl,benzoisoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl,phthalazinyl, pteridinyl, purinyl, naphthyridinyl, cinnolinyl,thieno[2,3-d]imidazole, 1,5-dihydro-benzo[b][1,4]diazepin-2-on-yl,pyrrolopyrimidinyl, azepanyl, azetidinyl, aziridinyl, azocanyl,morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, pyrrolinyl,dihydrothiazolyl, dihydropyridinyl, thiomorpholinyl, dioxanyl,dithianyl, tetrahydrofuryl, dihydropyranyl, tetrahydropyranyl, and[1,3]dioxolanyl.

Preferred heterocycles for R₆ are pyrazolyl, pyrimidinyl, pyrimidinonyl,pyridinyl, pyridazinonyl, and quinolinyl, wherein each ring issubstituted with 0, 1, or 2 substituents selected from methoxy andmethyl.

L_(3a) and L_(3b) are each independently selected from a bond, —O—,alkylene, —C(═O)—, —S—, —SO₂N(R_(14a))—, —N(R_(14a))SO²⁻—,—C(O)N(R_(14a))—, —N(R_(14a))C(O)—, and —N(R₁₅)—. Preferably, L_(3a) isa bond. L_(3b) also is preferred to be a bond.

A preferred aryl group at R_(6a) is cyanophenyl. Preferably, R_(6a) is aheterocycle. Examples of suitable heterocycles for R_(6a) include, butare not limited to pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl,pyrimidinyl, pyrrolyl, pyridazinonyl, pyridonyl, pyrimidinonyl,pyrrolidinyl, pyrrolinyl and quinolinyl. More preferred heterocycles forR_(6a) are pyrazolyl, pyrimidinyl, pyrimidinonyl, pyridinyl,pyridazinonyl, and quinolinyl wherein each ring is substituted with 0,1, or 2 substituents selected from methoxy and methyl.

A preferred aryl group at R_(6b) is cyanophenyl. Preferably, R_(6b) is aheterocycle. Examples of suitable heterocycles for R_(6b) include, butare not limited to, furyl, imidazolyl, isoxazolyl, isothiazolyl,oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl,pyrrolyl, tetrazolyl, thiadiazolyl, thiadiazolonyl, thiadiazinonyl,oxadiazolyl, oxadiazolonyl, oxadiazinonyl, thiazolyl, thienyl,triazinyl, triazolyl, triazolyl, pyridazinonyl, pyridonyl,pyrimidinonyl, indolyl, benzothienyl, benzofuranyl, indazolyl,benzimidazolyl, benzothiazolyl, benzoxazolyl, benzoisothiazolyl,benzoisoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl,phthalazinyl, pteridinyl, purinyl, naphthyridinyl, cinnolinyl,thieno[2,3-d]imidazole, pyrrolopyrimidinyl, azepanyl, azetidinyl,aziridinyl, azocanyl, morpholinyl, piperazinyl, piperidinyl,pyrrolidinyl, pyrrolinyl, dihydrothiazolyl, dihydropyridinyl,thiomorpholinyl, dioxanyl, dithianyl, tetrahydrofuryl, dihydropyranyl,tetrahydropyranyl, and [1,3]dioxolanyl. More preferred heterocycles forR_(6b) are pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl,pyrrolyl, pyridazinonyl, pyridonyl, pyrimidinonyl, pyrrolidinyl,pyrrolinyl and quionolyl, wherein each ring is substituted with 0, 1, or2 substituents selected from methoxy and methyl.

R_(3a) and R_(3b) are each independently hydrogen, cyano, halogen,alkyl, cycloalkyl, fluoroalkyl, alkoxy, alkoxyalkyl, fluoroalkoxy,alkylthio, SO₂N(R_(14a))(R_(14b)), or —N(R_(14a))SO₂(R_(14b)). R_(3a)and R_(3b) are both preferred to be hydrogen.

In one embodiment, R₄ and R₅ are each independently alkyl, fluoroalkyl,hydroxyalkyl, alkoxyalkyl, or cycloalkyl. In this embodiment, R₄ and R₅are preferably alkyl or hydroxyalkyl, and more particularly methyl,ethyl, propyl, and hydroxyethyl. Groups selected for R₄ and R₅ need notbe the same.

Alternatively, R₄ and R₅ are taken together with the nitrogen atom towhich each is attached form a non-aromatic ring. The non-aromatic ringform can be any nitrogen-containing non-aromatic ring. Examples ofnon-aromatic rings suitable for the embodiment wherein R₄ and R₅ aretaken together to form a ring include, but are not limited to,non-aromatic rings having the formulas:

Q₁ is O, S, —N(R₂₀)—, or C;

Q₂ is —N(R₂₀)— or C;

Q₃ is N or C;

R₂₀ is selected from the group consisting of hydrogen, alkyl andalkylcarbonyl;

p1 and p2 are each independently 1, 2 or 3;

q1, q2, q3, q4, and q5 are each independently 0, 1, or 2; and

r1, r2 and r3 are each independently 1 or 2;

wherein each carbon atom in the ring is substituted with hydrogen, orwith 0, 1, or 2 substituents independently selected at each occurrencefrom the group consisting of hydroxy, fluoro, alkyl, hydroxyalkyl,fluoroalkyl, cycloalkyl, cyano, fluoroalkoxy, alkoxyalkyl, alkoxy,fluoroalkoxy, haloalkyl, and —N(R_(21a))(R_(21b)), wherein R_(21a) andR_(21b) are each independently selected from the group consisting ofhydrogen, alkyl, and alkylcarbonyl.

Preferred groups for forming the ring of R₄ and R₅ have the formula (a)or (b). More particularly, R₄ and R₅ are taken together with thenitrogen atom to which each is attached to form azepanyl, azetidinyl,aziridinyl, azocanyl, morpholinyl, piperazinyl, piperidinyl,pyrrolidinyl, pyrrolinyl, and hexahydropyrrolo[3,4-b]pyrrolyl, whereineach group is substituted with 0, 1, or 2 substituents selected fromalkyl, hydroxyalkyl, hydroxy, fluoro and fluoroalkyl.

Preferred rings of the formula (a) are piperidine, pyrrolidine,4-fluoropiperidine, 4-hydroxypiperidine, 2-methylpiperidine,(2R)-methylpyrrolidine ring and (2S)-methylpyrrolidine ring.

A preferred ring of the formula (b) is

Q₂ is —N(R₂₀)—;

wherein q₁, q₂, q₃, and q₄ are each 1; and R₂₀ is hydrogen or alkyl. Inanother embodiment q₁ is 0, q₂ is 2 and q₃ and q₄ are each 1.

Another embodiment of the invention is compounds of the formula (II):

wherein R₁, R₂, R_(3a), R_(3b), R₄, and R₅ are as described forcompounds of formula (I). In one embodiment, R₁ is —L₂—R₆, R₂ ishydrogen, R_(3a) and R_(3b) are both hydrogen, and R₄ and R₅ takentogether form a non-aromatic ring. In another embodiment, R₁ ishydrogen, R₂ is —L₂—R₆, R_(3a) and R_(3b) are both hydrogen, and R₄ andR₅ taken together form a non-aromatic ring.

Another embodiment of the invention is compounds of the formula (III):

wherein R₁, R₂, R_(3a), R_(3b), R₄, and R₅ are as described forcompounds of formula (I). In one embodiment, R₁ is —L₂—R₆, R₂ ishydrogen, R_(3a) and R_(3b) are both hydrogen, and R₄ and R₅ takentogether form a non-aromatic ring. In another embodiment, R₁ ishydrogen, R₂ is —L₂—R₆, R_(3a) and R_(3b) are both hydrogen, and R₄ andR₅ taken together form a non-aromatic ring.

Suitable groups for each position in compounds of formula (I), forexample, R₁, R₂, R_(3a), R_(3b), R₄, and R₅, and the integer representedby m, in all embodiments, each can be determined independently ofsubstitutions in other positions of the compound. It is contemplatedthat a preferred group represented by one variable, for example R₁ is—L₂R₆ wherein L₂ is a defined for R₁ and R₆ is heterocycle, can beincorporated into compounds of formula (I) with a preferred group foranother variable, for example wherein R₄ and R₅ is a group of formula(d) as previously described from R₄ and R₅.

One embodiment contemplated as part of the invention includes, but isnot limited to, compounds of formula (I) wherein m is 0; L is a bond; L₂is a bond, —O—, alkylene, —C(═O)—, —S—, —SO₂N(R_(14a))—,N(R_(14a))SO²⁻—, —C(O)N(R_(14a))—, —N(R_(14a))C(O)—, or —N(R₁₅)—,wherein R_(14a), R_(14b), and R₁₅ are as previously defined forcompounds of formula (I); and R₆ is heterocycle.

One embodiment contemplated as part of the invention includes, but isnot limited to, compounds of formula (I) wherein m is 0, L is a bond, L₂is a bond, and R₆ is heterocycle.

Another specific embodiment contemplated as part of the inventionincludes, but is not limited to, compounds of formula (I) wherein m is0; L₂ is a bond, —O—, alkylene, —C(═O)—, —S—, —SO₂N(R_(14a))—,—N(R_(14a))SO²⁻—, C(O)N(R_(14a))—, —N(R_(14a))C(O)—, or —N(R₁₅)—,wherein R_(14a), R_(14b), and R₁₅ are as previously defined forcompounds of formula (I); R₆ is heterocycle; and R₄ and R₅ are takentogether to form a non-aromatic ring of the structure (a), (b), or (c),as previously described for R₄ and R₅.

Another specific embodiment contemplated as part of the inventionincludes, but is not limited to, compounds of formula (I) wherein m is0, L₂ is a bond, R₆ is heterocycle, and R₄ and R₅ are taken together toform a non-aromatic ring of the structure (a), (b), or (c), aspreviously described for R₄ and R₅.

Another specific embodiment contemplated as part of the inventionincludes, but is not limited to, compounds of formula (I) wherein m is0, L is a bond, R₆ is heterocycle, and R₄ and R₅ are taken together toform a non-aromatic ring of the structure (a), (c), or (d), aspreviously described for R₄ and R₅.

Another embodiment of preferred compounds are compounds of formula (I)wherein R₁ or R₂ is L₂R₆, L₂ is a bond, and R₆ is a structure offormula:

wherein R₁₆ and R₁₇ each are independently selected from hydrogen,alkyl, haloalkyl, cycloalkyl, alkoxyalkyl, aryl, and heteroaryl; or R₁₆and R₁₇ taken together with the carbon atom to which each is attachedform a 3- to 7-membered ring; v is 1, 2, 3, 4, 5, or 6; and all othervariables are as defined for compounds of formula (I).

Specific embodiments contemplated as part of the invention also include,but are not limited to, compounds of formula (I), as defined, forexample:

-   Trans-2-{3-[(2R)-2-methylpyrrolidin-1-yl]cyclobutyl}-6-pyrimidin-5-yl-1,3-benzothiazole;-   Trans-6-(2,6-dimethylpyridin-3-yl)-2-{3-[(2R)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazole;-   Trans-6-(2,4-dimethoxypyrimidin-5-yl)-2-{3-[(2R)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazole;-   Trans-6-(2-methoxypyrimidin-5-yl)-2-{3-[(2R)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazole;-   Trans-2-{3-[(2R)-2-methylpyrrolidin-1-yl]cyclobutyl}-6-pyridin-4-yl-1,3-benzothiazole;-   Trans-6-(6-methoxypyridin-3-yl)-2-{3-[(2R)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazole;-   Trans-2-{3-[(2R)-2-methylpyrrolidin-1-yl]cyclobutyl}-6-pyridin-3-yl-1,3-benzothiazole;-   Trans-3-(2-{3-[(2R)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazol-6-yl)quinoline;-   Trans-6-(6-fluoropyridin-3-yl)-2-{3-[(2R)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazole;-   Trans-4-(2-{3-[(2R)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazol-6-yl)benzonitrile;-   Trans-2-{3-[(2S)-2-methylpyrrolidin-1-yl]cyclobutyl}-6-pyrimidin-5-yl-1,3-benzothiazole;-   Trans-6-(2,4-dimethoxypyrimidin-5-yl)-2-{3-[(2S)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazole;-   Trans-6-(2,6-dimethylpyridin-3-yl)-2-{3-[(2S)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazole;-   Trans-6-(2-methoxypyrimidin-5-yl)-2-{3-[(2S)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazole;-   Trans-6-(6-methoxypyridin-3-yl)-2-{3-[(2S)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazole;-   Trans-3-(2-{3-[(2S)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazol-6-yl)quinoline;-   Cis-2-{3-[(2R)-2-methylpyrrolidin-1-yl]cyclobutyl}-6-pyrimidin-5-yl-1,3-benzothiazole;-   Cis-6-(2,6-dimethylpyridin-3-yl)-2-{3-[(2R)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazole;-   Cis-2-{3-[(2S)-2-methylpyrrolidin-1-yl]cyclobutyl}-6-pyrimidin-5-yl-1,3-benzothiazole;-   Cis-6-(2,4-dimethoxypyrimidin-5-yl)-2-{3-[(2S)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazole;-   Cis-6-(2,6-dimethylpyridin-3-yl)-2-{3-[(2S)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazole;-   Trans-2-(2-{3-[(2R)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazol-6-yl)pyridazin-3(2H)-one;-   Trans-6-methyl-2-(2-{3-[(2R)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazol-6-yl)pyridazin-3(2H)-one;-   Trans-5-methyl-1-(2-{3-[(2R)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazol-6-yl)pyridin-2(1H)-one;-   Trans-3-methyl-1-(2-{3-[(2R)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazol-6-yl)pyridin-2(1H)-one;-   Trans-2-(2-{3-[(2S)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazol-6-yl)pyridazin-3(2H)-one;-   Trans-6-methyl-2-(2-{3-[(2S)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazol-6-yl)pyridazin-3(2H)-one;-   Trans-5-methyl-1-(2-{3-[(2S)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazol-6-yl)pyridin-2(1H)-one;-   Trans-3-methyl-1-(2-{3-[(2S)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazol-6-yl)pyridin-2(1H)-one;-   Cis-6-pyrimidin-5-yl-2-(3-pyrrolidin-1-ylcyclobutyl)-1,3-benzothiazole;-   Cis-6-(2-methoxypyrimidin-5-yl)-2-(3-pyrrolidin-1-ylcyclobutyl)-1,3-benzothiazole;-   Cis-2-(3-piperidin-1-ylcyclobutyl)-6-pyrimidin-5-yl-1,3-benzothiazole-   Cis-6-(2-methoxypyrimidin-5-yl)-2-(3-piperidin-1-ylcyclobutyl)-1,3-benzothiazole;-   Cis-2-(3-azepan-1-ylcyclobutyl)-6-pyrimidin-5-yl-1,3-benzothiazole;-   Cis-2-(3-morpholin-4-ylcyclobutyl)-6-pyrimidin-5-yl-1,3-benzothiazole;-   Cis-{(2S)-1-[3-(6-pyrimidin-5-yl-1,3-benzothiazol-2-yl)cyclobutyl]pyrrolidin-2-yl}methanol;-   Cis-((2S)-1-{3-[6-(2-methoxypyrimidin-5-yl)-1,3-benzothiazol-2-yl]cyclobutyl}pyrrolidin-2-yl)methanol;-   Cis-2-{3-[(3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]cyclobutyl}-6-pyrimidin-5-yl-1,3-benzothiazole;-   Cis-2-{3-[(3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]cyclobutyl}-6-(2-methoxypyrimidin-5-yl)-1,3-benzothiazole;-   Cis-2-{3-[(2R)-2-methylpiperidin-1-yl]cyclobutyl}-6-pyrimidin-5-yl-1,3-benzothiazole;-   Cis-N-isopropyl-N-methyl-N-[3-(6-pyrimidin-5-yl-1,3-benzothiazol-2-yl)cyclobutyl]amine;-   Cis-{1-[3-(6-pyrimidin-5-yl-1,3-benzothiazol-2-yl)cyclobutyl]piperidin-4-yl}methanol;-   Trans-{1-[3-(6-pyrimidin-5-yl-1,3-benzothiazol-2-yl)cyclobutyl]piperidin-4-yl}methanol;-   Trans-2-(3-piperidin-1-ylcyclobutyl)-6-pyrimidin-5-yl-1,3-benzothiazole;-   Trans-6-(2,6-dimethylpyridin-3-yl)-2-(3-piperidin-1-ylcyclobutyl)-1,3-benzothiazole;-   Trans-6-(6-methoxypyridin-3-yl)-2-(3-piperidin-1-ylcyclobutyl)-1,3-benzothiazole;-   Trans-6-(2-methoxypyrimidin-5-yl)-2-(3-piperidin-1-ylcyclobutyl)-1,3-benzothiazole;-   Trans-2-[2-(3-piperidin-1-ylcyclobutyl)-1,3-benzothiazol-6-yl]pyridazin-3(2H)-one;-   Cis-2-[2-(3-piperidin-1-ylcyclobutyl)-1,3-benzothiazol-6-yl]pyridazin-3(2H)-one;-   Trans-6-methyl-2-[2-(3-piperidin-1-ylcyclobutyl)-1,3-benzothiazol-6-yl]pyridazin-3(2H)-one;-   Trans-3-methyl-1-[2-(3-piperidin-1-ylcyclobutyl)-1,3-benzothiazol-6-yl]pyridin-2(1H)-one;-   Trans-6-(1-methyl-1H-pyrazol-4-yl)-2-(3-piperidin-1-ylcyclobutyl)-1,3-benzothiazole;-   Trans-N-isopropyl-N-methyl-N-[3-(6-pyrimidin-5-yl-1,3-benzothiazol-2-yl)cyclobutyl]amine;-   Trans-N-isopropyl-N-{3-[6-(2-methoxypyrimidin-5-yl)-1,3-benzothiazol-2-yl]cyclobutyl}-N-methylamine;-   Trans-N-isopropyl-N-{3-[6-6-methoxypyridin-3-yl)-1,3-benzothiazol-2-yl]cyclobutyl}-N-methylamine;-   Trans-N-isopropyl-N-{3-[6-(2-methoxypyridin-3-yl)-1,3-benzothiazol-2-yl]cyclobutyl}-N-methylamine;-   Trans-N-{3-[6-(2,6-dimethylpyridin-3-yl)-1,3-benzothiazol-2-yl]cyclobutyl}-N-isopropyl-N-methylamine;-   Trans-2-(2-{3-[isopropyl(methyl)amino]cyclobutyl}-1,3-benzothiazol-6-yl)pyridazin-3(2H)-one;-   Trans-2-(2-{3-[isopropyl(methyl)amino]cyclobutyl}-1,3-benzothiazol-6-yl)-6-methylpyridazin-3(2H)-one;-   Trans-1-(2-{3-[isopropyl(methyl)amino]cyclobutyl}-1,3-benzothiazol-6-yl)-3-methylpyridin-2(1H)-one;-   Trans-1-(2-{3-[isopropyl(methyl)amino]cyclobutyl}-1,3-benzothiazol-6-yl)-5-methylpyridin-2(1H)-one;-   Trans-2-(3-azetidin-1-ylcyclobutyl)-6-pyrimidin-5-yl-1,3-benzothiazole;-   Trans-6-pyrimidin-5-yl-2-(3-pyrrolidin-1-ylcyclobutyl)-1,3-benzothiazole;-   Trans-6-(2,6-dimethylpyridin-3-yl)-2-(3-pyrrolidin-1-ylcyclobutyl)-1,3-benzothiazole;-   Trans-6-(2-methoxypyrimidin-5-yl)-2-(3-pyrrolidin-1-ylcyclobutyl)-1,3-benzothiazole;-   Trans-6-(2,4-dimethoxypyrimidin-5-yl)-2-(3-pyrrolidin-1-ylcyclobutyl)-1,3-benzothiazole;-   Trans-6-(6-methoxypyridin-3-yl)-2-(3-pyrrolidin-1-ylcyclobutyl)-1,3-benzothiazole;-   Trans-2-[2-(3-pyrrolidin-1-ylcyclobutyl)-1,3-benzothiazol-6-yl]pyridazin-3(2H)-one;-   Trans-6-methyl-2-[2-(3-pyrrolidin-1-ylcyclobutyl)-1,3-benzothiazol-6-yl]pyridazin-3(2H)-one;-   Trans-5-methyl-1-[2-(3-pyrrolidin-1-ylcyclobutyl)-1,3-benzothiazol-6-yl]pyridin-2(1H)-one;-   Trans-3-methyl-1-[2-(3-pyrrolidin-1-ylcyclobutyl)-1,3-benzothiazol-6-yl]pyridin-2(1H)-one;-   Trans-2-(3-azepan-1-ylcyclobutyl)-6-pyrimidin-5-yl-1,3-benzothiazole;-   Trans-2-(3-morpholin-4-ylcyclobutyl)-6-pyrimidin-5-yl-1,3-benzothiazole;-   Trans-2-{3-[(2S)-2-(fluoromethyl)pyrrolidin-1-yl]cyclobutyl}-6-pyrimidin-5-yl-1,3-benzothiazole;-   Trans-{(2S)-1-[3-(6-pyrimidin-5-yl-1,3-benzothiazol-2-yl)cyclobutyl]pyrrolidin-2-yl}methanol;-   Trans-((2S)-1-{3-[6-(2,6-dimethylpyridin-3-yl)-1,3-benzothiazol-2-yl]cyclobutyl}pyrrolidin-2-yl)methanol;-   Trans-2-[3-(2-methylpiperidin-1-yl)cyclobutyl]-6-pyrimidin-5-yl-1,3-benzothiazole;-   Trans-2-(3-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-ylcyclobutyl)-6-pyrimidin-5-yl-1,3-benzothiazole;-   Trans-2-[3-(4-fluoropiperidin-1-yl)cyclobutyl]-6-pyrimidin-5-yl-1,3-benzothiazole;-   Trans-2-[3-(4-fluoropiperidin-1-yl)cyclobutyl]-6-(2-methoxypyrimidin-5-yl)-1,3-benzothiazole;-   Trans-6-(2,6-dimethylpyridin-3-yl)-2-[3-(4-fluoropiperidin-1-yl)cyclobutyl]-1,3-benzothiazole;-   Trans-(3R)-1-[3-(6-pyrimidin-5-yl-1,3-benzothiazol-2-yl)cyclobutyl]piperidin-3-ol;-   Trans-N-ethyl-N-propyl-N-[3-(6-pyrimidin-5-yl-1,3-benzothiazol-2-yl)cyclobutyl]amine;-   Trans-Diethyl-[3-(6-pyrimidin-5-yl-benzothiazol-2-yl)-cyclobutyl]-amine;-   Trans-Diethyl-{3-[6-(2-methoxy-pyrimidin-5-yl)-benzothiazol-2-yl]-cyclobutyl}-amine;-   Trans-{3-[6-(2-Methoxy-pyrimidin-5-yl)-benzothiazol-2-yl]-cyclobutyl}-methyl-propyl-amine;-   Trans-{3-[6-(2,6-Dimethyl-pyridin-3-yl)-benzothiazol-2-yl]-cyclobutyl}-methyl-propyl-amine;-   Trans-Methyl-{3-[6-(1-methyl-1H-pyrazol-4-yl)-benzothiazol-2-yl]-cyclobutyl}-propyl-amine;-   Trans-2-(Ethyl-{3-[6-(2-methoxy-pyrimidin-5-yl)-benzothiazol-2-yl]-cyclobutyl}-amino)-ethanol;-   Trans-2-({3-[6-(2,6-Dimethyl-pyridin-3-yl)-benzothiazol-2-yl]-cyclobutyl}-ethyl-amino)-ethanol;-   6-Pyrimidin-5-yl-2-(3-pyrrolidin-1-ylmethyl-cyclobutyl)-benzothiazole;-   Trans-5-(2,6-Dimethyl-pyridin-3-yl)-2-[3-(2-methyl-pyrrolidin-1-yl)-cyclobutyl]-benzothiazole;-   Trans-5-(2,4-Dimethoxy-pyrimidin-5-yl)-2-[3-(2-methyl-pyrrolidin-1-yl)-cyclobutyl]-benzothiazole;-   Trans-6-(1-Methyl-1H-pyrazol-4-yl)-2-[3-(2-methyl-pyrrolidin-1-yl)-cyclobutyl]-benzothiazole;-   Trans-2-[3-(4-Fluoro-piperidin-1-yl)-cyclobutyl]-6-(1-methyl-1H-pyrazol-4-yl)-benzothiazole;-   Trans-2-(3-azetidin-1-ylcyclobutyl)-6-(2-methoxypyrimidin-5-yl)-1,3-benzothiazole;-   Trans-2-(3-azetidin-1-ylcyclobutyl)-6-(2,6-dimethylpyridin-3-yl)-1,3-benzothiazole;-   Trans-2-(3-azetidin-1-ylcyclobutyl)-6-(1-methyl-1H-pyrazol-4-yl)-1,3-benzothiazole;-   Trans-2-(3-azepan-1-ylcyclobutyl)-6-(2-methoxypyrimidin-5-yl)-1,3-benzothiazole;-   Trans-2-(3-azepan-1-ylcyclobutyl)-6-(2,6-dimethylpyridin-3-yl)-1,3-benzothiazole;-   Trans-2-(3-azepan-1-ylcyclobutyl)-6-(1-methyl-1H-pyrazol-4-yl)-1,3-benzothiazole;-   Cis-N-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-acetamide;-   Cis-2-Chloro-N-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-acetamide;-   Cis-N-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-propionamide;-   Cis-N-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-isobutyramide;-   Cis-Cyclopropanecarboxylic    acid[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-amide;-   Cis-Cyclobutanecarboxylic    acid[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-amide;-   Cis-Cyclopentanecarboxylic    acid[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-amide;-   Cis-Cyclohexanecarboxylic    acid[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-amide;-   Cis-Furan-2-carboxylic    acid[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-amide;-   Cis-4-Cyano-N-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-benzamide;-   Cis-4-Cyano-N-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-benzenesulfonamide;-   Cis-Thiophene-2-sulfonic    acid-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-amide;-   113 Cis-Thiophene-2-carboxylic    acid-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-amide;-   Cis-Thiophene-2-carboxylic    acid-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-amide;-   Cis-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-carbamic    acid isobutyl ester;-   Cis-Morpholine-4-carboxylic    acid-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-amide;-   Cis-Pyrazine-2-carboxylic    acid-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-amide;-   Cis-N-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-2-thiophen-3-yl-acetamide;-   Cis-N-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-3-thiophen-2-yl-propionamide;-   Cis-3-Furan-2-yl-N-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-propionamide;-   Cis-Pyrimidine-5-carboxylic    acid-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-amide;-   Trans-4-Cyano-N-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-benzamide;-   Trans-N-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-propionamide;-   Trans-N-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-isobutyramide;-   Trans-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-carbamic    acid isobutyl ester;-   Trans-Cyclopropanecarboxylic    acid[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-amide;-   Trans-Cyclobutanecarboxylic    acid[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-amide;-   Trans-Cyclopentanecarboxylic    acid[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-amide;-   Trans-Cyclohexanecarboxylic    acid[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-amide;-   Trans-Furan-2-carboxylic    acid[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-amide;-   Trans-Morpholine-4-carboxylic    acid-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-amide;-   Trans-Pyrimidine-5-carboxylic    acid-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-amide;-   Trans-Pyrazine-2-carboxylic    acid-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-amide;-   Racemic-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-pyrimidin-5-yl-amine;-   Racemic-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-pyrimidin-2-yl-amine;-   Racemic-(5-bromo-pyrimidin-2-yl)-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-amine;-   Racemic-(5-methyl-pyridin-2-yl)-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-amine;-   Racemic-6-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-ylamino]-nicotinonitrile;-   Racemic-6-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-ylamino]-nicotinonitrile;-   2{Trans-3-[(S)-2-methylpiperidin-1-yl]cyclobutyl}-1,3-benzothiazol-6-yl-azetidin-2-one;-   2-{Trans-3-[(S)-2-methylpiperidin-1-yl]cyclobutyl}-1,3-benzothiazol-6-yl-pyrrolidin-2-one;-   2{Trans-3-[(S)-2-methylpiperidin-1-yl]cyclobutyl}-1,3-benzothiazol-6-yl-piperidin-2-one;-   2{Trans-3-[(S)-2-methylpiperidin-1-yl]cyclobutyl}-1,3-benzothiazol-6-yl-homopyrrolidin-2-one;-   2-{Trans-3-[(S)-2-methylpiperidin-1-yl]cyclobutyl}-1,3-benzothiazole-6-carboxamide;-   N-Isopropyl-2-{trans-3-[(S)-2-methylpiperidin-1-yl]cyclobutyl}-1,3-benzothiazole-6-carboxamide;-   N-cyclopropyl-2-{trans-3-[(S)-2-methylpiperidin-1-yl]cyclobutyl}-1,3-benzothiazole-6-carboxamide;-   N-phenyl-2-{trans-3-[(S)-2-methylpiperidin-1-yl]cyclobutyl}-1,3-benzothiazole-6-carboxamide;-   N-thiazol-2-yl-2-{trans-3-[(S)-2-methylpiperidin-1-yl]cyclobutyl}-1,3-benzothiazole-6-carboxamide;-   N-benzyl-2-{trans-3-[(S)-2-methylpiperidin-1-yl]cyclobutyl}-1,3-benzothiazole-6-carboxamide;-   N-(2-phenethyl)-2-{trans-3-[(S)-2-methylpiperidin-1-yl]cyclobutyl}-1,3-benzothiazole-6-carboxamide;-   N,N-dimethyl-2-{trans-3-[(S)-2-methylpiperidin-1-yl]cyclobutyl}-1,3-benzothiazole-6-carboxamide;-   (Pyrrolidin-1-yl)-2-{trans-3-[(S)-2-methylpiperidin-1-yl]cyclobutyl}-1,3-benzothiazole-6-methanone;-   2-[Trans-3-(piperidin-1-yl)cyclobutyl]-1,3-benzothiazol-6-yl-3-methyl-pyrrolidin-2-one;-   2-[Trans-3-(piperidin-1-yl)cyclobutyl]-1,3-benzothiazol-6-yl-oxazolidin-2-one;    and-   2-[Trans-3-(piperidin-1-yl)cyclobutyl]-1,3-benzothiazol-6-yl-3-methylimidazolidin-2-one;-   Trans-6-bromo-2-{3-[(2R)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazole;-   Trans-6-bromo-2-{3-[(2S)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazole;-   Cis-6-bromo-2-{3-[(2R)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazole;-   Cis-6-bromo-2-(3-pyrrolidin-1-ylcyclobutyl)-1,3-benzothiazole;-   Cis-6-bromo-2-(3-piperidin-1-ylcyclobutyl)-1,3-benzothiazole;-   Cis-2-(3-azepan-1-ylcyclobutyl)-6-bromo-1,3-benzothiazole;-   Cis-{(2S)-1-[3-(6-bromo-1,3-benzothiazol-2-yl)cyclobutyl]pyrrolidin-2-yl}methanol;-   Cis-tert-butyl(3aR,6aR)-5-[3-(6-bromo-1,3-benzothiazol-2-yl)cyclobutyl]hexahydropyrrolo[3,4-b]pyrrole-1(2H)-carboxylate;-   Cis-6-bromo-2-{3-[(2R)-2-methylpiperidin-1-yl]cyclobutyl}-1,3-benzothiazole;-   Cis-N-[3-(6-bromo-1,3-benzothiazol-2-yl)cyclobutyl]-N-isopropyl-N-methylamine;-   Cis-{1-[3-(6-bromo-1,3-benzothiazol-2-yl)cyclobutyl]piperidin-4-yl}methanol;-   Trans-{1-[3-(6-bromo-1,3-benzothiazol-2-yl)cyclobutyl]piperidin-4-yl}methanol;-   Trans-6-bromo-2-(3-piperidin-1-ylcyclobutyl)-1,3-benzothiazole;-   Trans-N-[3-(6-bromo-1,3-benzothiazol-2-yl)cyclobutyl]-N-isopropyl-N-methylamine;-   Trans-2-(3-azetidin-1-ylcyclobutyl)-6-bromo-1,3-benzothiazole;-   Trans-6-bromo-2-(3-pyrrolidin-1-ylcyclobutyl)-1,3-benzothiazole;-   Trans-2-(3-azepan-1-ylcyclobutyl)-6-bromo-1,3-benzothiazole;-   Trans-6-bromo-2-(3-morpholin-4-ylcyclobutyl)-1,3-benzothiazole;-   Trans-6-bromo-2-{3-[(2S)-2-(fluoromethyl)pyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazol;-   Trans-{(2S)-1-[3-(6-bromo-1,3-benzothiazol-2-yl)cyclobutyl]pyrrolidin-2-yl}methanol;-   Trans-6-bromo-2-[3-(2-methylpiperidin-1-yl)cyclobutyl]-1,3-benzothiazole;-   Trans-tert-butyl    5-[3-(6-bromo-1,3-benzothiazol-2-yl)cyclobutyl]hexahydropyrrolo[3,4-b]pyrrole-1(2H)-carboxylate;-   Trans-6-bromo-2-[3-(4-fluoropiperidin-1-yl)cyclobutyl]-1,3-benzothiazole;-   Trans-[3-(6-Bromo-benzothiazol-2-yl)-cyclobutyl]-diethyl-amine;-   Trans-[3-(6-Bromo-benzothiazol-2-yl)-cyclobutyl]-methyl-propyl-amine;-   Trans-2-{[3-(6-Bromo-benzothiazol-2-yl)-cyclobutyl]-ethyl-amino}-ethanol;-   6-Bromo-2-(3-pyrrolidin-1-ylmethyl-cyclobutyl)-benzothiazole and-   Trans-5-Chloro-2-[3-(2-methyl-pyrrolidin-1-yl)-cyclobutyl]-benzothiazole.

Preferred compounds of formula (I), (II), or (III) include at least:

-   Trans-2-(3-piperidin-1-ylcyclobutyl)-6-pyrimidin-5-yl-1,3-benzothiazole;-   Trans-Diethyl-{3-[6-(2-methoxy-pyrimidin-5-yl)-benzothiazol-2-yl]-cyclobutyl}-amine;-   Trans-2-(Ethyl-{3-[6-(2-methoxy-pyrimidin-5-yl)-benzothiazol-2-yl]-cyclobutyl}-amino)-ethanol;-   Trans-2-[2-(3-piperidin-1-ylcyclobutyl)-1,3-benzothiazol-6-yl]pyridazin-3(2H)-one;    and-   Cis-2-[2-(3-piperidin-1-ylcyclobutyl)-1,3-benzothiazol-6-yl]pyridazin-3(2H)-one.

Compound names are assigned by using AUTONOM naming software, which isprovided by MDL Information Systems GmbH (formerly known as BeilsteinInformationssysteme) of Frankfurt, Germany, and is part of the CHEMDRAW®ULTRA v. 6.0.2 software suite.

Compounds of the invention may exist as stereoisomers wherein,asymmetric or chiral centers are present. These stereoisomers are “R” or“S” depending on the configuration of substituents around the chiralcarbon atom. The terms “R” and “S” used herein are configurations asdefined in IUPAC 1974 Recommendations for Section E, FundamentalStereochemistry, in Pure Appl. Chem., 1976, 45: 13-30. The inventioncontemplates various stereoisomers and mixtures thereof and these arespecifically included within the scope of this invention. Stereoisomersinclude enantiomers and diastereomers, and mixtures of enantiomers ordiastereomers. Individual stereoisomers of compounds of the inventionmay be prepared synthetically from commercially available startingmaterials which contain asymmetric or chiral centers or by preparationof racemic mixtures followed by resolution well-known to those ofordinary skill in the art. These methods of resolution are exemplifiedby (1) attachment of a mixture of enantiomers to a chiral auxiliary,separation of the resulting mixture of diastereomers byrecrystallization or chromatography and optional liberation of theoptically pure product from the auxiliary as described in Fumiss,Hannaford, Smith, and Tatchell, “Vogel's Textbook of Practical OrganicChemistry”, 5th edition (1989), Longman Scientific & Technical, EssexCM20 2JE, England, or (2) direct separation of the mixture of opticalenantiomers on chiral chromatographic columns or (3) fractionalrecrystallization methods.

Compounds of the invention may exist as cis or trans isomers, whereinsubstituents on a ring may attached in such a manner that they are onthe same side of the ring (cis) relative to each other, or on oppositesides of the ring relative to each other (trans). For example,cyclobutanes may be present in the cis or trans configuration, and maybe present as a single isomer or a mixture of the cis and trans isomers.Individual cis or trans isomers of compounds of the invention may beprepared synthetically from commercially available starting materialsusing selective organic transformations, or by prepared in singleisomeric form by purification of mixtures of the cis and trans isomers.Such methods are well-known to those of ordinary skill in the art, andmay include separation of isomers by recrystallization orchromatography.

It should be understood that the compounds of the invention may possesstautomeric forms, as well as geometric isomers, and that these alsoconstitute an aspect of the invention. It is also understood that thecompounds of the invention may exist as isotopomers, wherein atoms mayhave different weights; for example, hydrogen and deuterium, or ¹²C and¹³C.

Methods for Preparing Compounds of the Invention

The compounds of the invention can be better understood in connectionwith the following synthetic schemes and methods which illustrate ameans by which the compounds can be prepared.

Abbreviations which have been used in the descriptions of the schemesand the examples that follow are: BINAP for2,2′-bis(diphenylphosphino)-1,1′-binaphthyl; Boc for butyloxycarbonyl;EtOAc for ethyl acetate; HPLC for high pressure liquid chromatography;IPA for isopropyl alcohol; Me for methyl; MeOH for methanol; Ms formethanesulfonyl; Pd for palladium; tBu for tert-butyl; TEA fortriethylamine; TFA for trifluoroacetic acid; THF for tetrahydrofuran;and Ts for para-toluenesulfonyl; rt for “room temperature” or ambienttemperature suitably ranging 20-30° C. Microwave heating wasaccomplished in a commercial microwave apparatus.

The compounds of this invention can be prepared by a variety ofsynthetic procedures. Representative procedures are shown in, but arenot limited to, Schemes 1-5.

Compounds of formula (3), wherein m, R₁, R₂, R_(3a). R_(3b), R₄, R₅, Lare as defined in formula (I), can be prepared as described in Scheme 1.Acid chlorides of formula (1), purchased or prepared using methodologiesknown to those of ordinary skill in the art, when treated with compoundsof formula (2) will provide compounds of formula (3) which arerepresentative of the compounds of the present invention.

Compounds of formula (4) containing a nitrile group when treated withsodium hydroxide under aqueous conditions will provide carboxylic acidsof formula (5). Carboxylic acid compounds of formula (5) when treatedwith sulfonyl chloride or oxalyl chloride will provide acid chlorides offormula (6). Compounds of formula (6) undergo a condensation tobenzothiazole compounds of formula (7) when treated with compounds offormula (2a). Compounds (2a) are defined as in formula (1) for R_(3a),R_(3b), and wherein at least one of X₁ and X₂ is chloro, iodo, or bromo,and the other is hydrogen, acyl, acyloxy, alkenyl, alkoxy, alkoxyalkoxy,alkoxyalkyl, alkoxycarbonyl, alkoxyimino, alkoxysulfonyl, alkyl,alkylcarbonyl, alkylsulfonyl, alkynyl, amido, carboxy, cyano,cycloalkyl, fluoroalkoxy, haloalkoxy, haloalkyl, halogen, hydroxy,hydroxyalkyl, mercapto, nitro, alkylthio, —NR_(A)R_(B),(NR_(A)R_(B))carbonyl, —SO₂N(R_(14a))(R_(14b)), N(R_(14a))SO₂(R_(14b)).Compounds of formula (7) when treated with osmium tetroxide or potassiumosmate and sodium periodate will provide the cyclobutanone compound offormula (8). The reduction of compounds of formula (8) using hydridereducing reagents such as, but not limited to lithiumtri-sec-butylborohydride (L-Selectride), in solvents such as but notlimited to THF, provides compounds of formula (9). Compounds of formula(9) when treated with triflic anhydride, mesyl chloride or tosylchloride in the presence of a base such as but not limited to potassiumcarbonate, triethylamine, diisopropylethylamine and the like, followedby treatment with an amine of formula R₄R₅NH, wherein R₄ and R₅ are asdefined in formula (I), will provide the compound of formula (10).

There are many suitable and readily available amines of formula R₄R₅NH,wherein R₄ and R₅ are as defined in formula (I). Examples of such aminesR₄R₅NH are exemplified, but not limited to, those shown in Table 1.

TABLE 1 Examples of readily available amines of formula R₄R₅NH.Commercial Source, Chemical Abstracts Number (CAS #), or AminesStructures Literature Reference 2-(R)- methyl- pyrrolidine L-tartrate

WO 2004043458; Y. Pu et al., Organic Process Research & Development,9(1), 45-50, 2005 2-(S)- methyl- pyrrolidine L-tartrate

Kim, Mahn-Joo, et al., Bioorg. Med. Chem. Lett. 6(1):71-76 (1996);Tetrahedron, 37:1861-1869 (1981). L-pyrolinol

CAS# 23356-96-9, Aldrich hexahydro- pyrrolo[3,4- b]pyrrole-1- carboxylicacid tert-butyl ester

Q. Li, et al., J. Med. Chem.; 39(16), 3070-3088, 1996 2-(R)- methyl-piperidine

Clariant Life Science Molecules Sandycroft Deeside Clwyd CH5 2PX UNITEDKINGDOM S-(+)-2- fluoromethyl- pyrrolidine

CAS # 460748-85-0, prepared according to the procedure that describedin: WO 2004043458 2-methyl- piperidine

CAS # 109-05-7, Aldrich 4-fluoro- piperidine hydrochloride

ABCR GmbH & CO. KG P.O. Box 21 01 35 76151 Karlsruhe GERMANY(R)-3-hydroxy- piperidine hydrochloride

CAS #198976-43-1, Aldrich Chemical Company, Inc. 1001 West Saint PaulAvenue Milwaukee, WI 53233 USA

The Suzuki reaction can be used to convert compounds of formula (10)containing an X₁ group that is I, Br or Cl into compounds of formula(11). Similarly, the Suzuki reaction will convert compounds of formula(10) which contains an X₂ group that is I, Br or Cl into compounds offormula (12). The Suzuki reaction is between a halogen compound such asthat of formula (10) and a boronic acid or boronic ester of formulaR_(x)—B(OR)₂ wherein R_(x) is aryl, heteroaryl, heterocyclyl, alkyl,alkenyl, or cycloalkyl and R is hydrogen or alkyl, and is conducted inthe presence of a metal catalyst such as, but not limited to, palladiumdiacetate, PdCl₂(PPh₃)₂, or Pd(PPh₃)₄, optionally with a palladiumligand added such as 2-(dicyclohexylphosphino)biphenyl,tri-t-Butylphosphine, or tris(2-furyl)phosphine and a base such as, butnot limited to aqueous K₃PO₄ or Na₂CO₃, or KF. Alternatively, pinacolborane reagents such as, but not limited to, those represented by theformula

can be used in place of boronic acids or esters in the Suzuki reaction.References describing the methodology may be found in the following: N.Miyaura et al., Chem. Rev. 95:2457 (1995) or references cited within thearticle.

There are many aryl, heteroaryl, and heterocyclic boronic acids andboronic acid esters that are available commercially or that can beprepared as described in the scientific literature of synthetic organicchemistry. Typical examples of boronic acid and boronic acid esterreagents for the synthesis of compounds of formula (I) are shown inTable 2.

TABLE 2 Examples of Boronic Acid and Boronic Acid Ester Reagents BoronicAcid or Boronic Acid Commercial Source, Chemical Ester Abstracts Number(CAS #), or Literature Reference 2-pyrimidinone-5-boronic acid CAS#373384-19-1 2-methoxypyrimidine-5-boronic Frontier Scientific, Inc.,Logan, acid UT, USA 1H-pyrimidine-2,4-dione-5- Specs, Fleminglaan, theboranic acid Netherlands CAS #70523-22-7; Schinazi, Raymond F.; Prusoff,William H., Synthesis of 5-(dihydroxyboryl)-2′- deoxyuridine and relatedboron-containing pyrimidines, Journal of Organic Chemistry (1985),50(6), 841-7. pyridine-3-boronic acid CAS #1692-25-7, FrontierScientific, Inc., Logan, UT, USA 2,4-dimethoxypyrimidine-5- CAS#89641-18-9, Frontier boronic acid Scientific, Inc., Logan, UT, USA2-methoxy-5-pyridine boronic Digital Specialty Chemicals, Dublin, acidNH; CAS #163105-89-3; New shelf- stable halo- and alkoxy- substitutedpyridylboronic acids and their Suzuki cross- coupling reactions to yieldheteroarylpyridines, Parry, Paul R.; Bryce, Martin R.; Tarbit, Brian,Department of Chemistry, Synthesis (2003), (7), 1035-1038;Functionalized Pyridylboronic Acids and Their Suzuki Cross-CouplingReactions To Yield Novel Heteroarylpyridines, Parry, Paul R.; Wang,Changsheng; Batsanov, Andrei S.; Bryce, Martin R.; Tarbit, Brian,Journal of Organic Chemistry (2002), 67(21), 7541-7543.pyrimidine-5-boronic acid CAS #109299-78-7, S. Gronowitz, et al., “Onthe synthesis of various thienyl- and selenienyl- pyrimidines”, Chem.Scr. 26(2): 305-309 (1986). pyrimidine-5-boronic acid, Umemoto, et al.,Angew. Chem. pinacol ester Int. Ed. 40(14): 2620-2622 (2001).2-methylpyridine-5-boronic SYNCHEM OHG acidhydrateHeinrich-Plett-Strassse 40; Kassel, D-34132; Germany; CAS #659742-21-92H-Pyran,3,6-dihydro-4- CAS # 287944-16-5; Murata,(4,4,5,5-tetramethyl-1,3,2- Miki; Oyama, Takashi; Watanabe,dioxaborolan-2-yl) Shinji; Masuda, Yuzuru, Synthesis of alkenylboronatesvia palladium- catalyzed borylation of alkenyl triflates (or iodides)with pinacolborane. Synthesis(2000), (6), 778-780.1(2H)-Pyridinecarboxylic acid, CAS # 286961-14-6; A3,6-dihydro-4-(4,4,5,5- versatile synthesis oftetramethyl-1,3,2-dioxaborolan- 4-aryltetrahydropyridines via2-yl)-,1,1-dimethylethyl ester palladium mediated Suzuki cross- couplingwith cyclic vinyl boronates, Eastwood, Paul R., Discovery Chemistry,Aventis Pharma, Essex, UK., Tetrahedron Letters (2000), 41(19),3705-3708. (5-cyano-3-pyridinyl)-boronic CAS #497147-93-0; Chemstep acidInstitut du PIN - University Bordeaux 1 351 cours de la liberationTalence Cedex, 33450 France Thianthrene-1-boronic acid Aldrich ChemicalCompany, Inc. Benzoxazole-5-boronic acid Cat # 110831, AsymchemLaboratories, Inc. Benzothiazole-5-boronic acid Cat # 1464, DigitalSpecialty Chemicals, Inc. 4-Methyl-7-(4,4,5,5-tetramethyl- Cat #CC13539CB, Acros Organics 1,3,2-dioxaborolan-2-yl)-3,4- USAdihydro-2h-1,4-benzoxazine 10-Methyl-3-(4,4,5,5- Kraemer, C. S.; et. al.Synthesis tetramethyl-[1,3,2]dioxaborolan- 2002, 9, 1163-1170.2-yl)-10H-phenothiazine (1,4-Dihydro-4,4-dimethyl-2- Zhang, P.; et. al.J. Med. Chem. oxo-2H-3,1-benzoxazin-6- 2002, 45, 4379-4382. yl)boronicacid

Boronic acids or boronic acid esters of formula R_(x)—B(OR)₂ and

can be prepared from corresponding halides or triflates of R_(x) viaeither: (1) metal exchange with an organo lithium agent followed withaddition of alkyl borate or pinacolborate or, (2) cross coupling with areagent such as, but not limited to, bis(pinacolato)diboron (CAS#73183-34-3) or bis(pinacolato)borane. References describing the firstmethod are: B. T. O'Neill, et al., Organic Letters, 2:4201 (2000); M. D.Sindkhedkar, et al., Tetrahedron, 57:2991 (2001); W. C. Black, et al.,J. Med. Chem., 42:1274 (1999); R. L. Letsinger et al., J. Amer. Chem.Soc., 81:498-501 (1959); and F. I. Carroll et al., J. Med. Chem.,2229-2237 (2001). References describing the second method are: T.Ishiyama et al., Tetrahedron, 57:9813-9816 (2001); T. Ishiyama et al.,J. Org. Chem., 60:7508-7510 (1995); and Takagi et al., TetrahedronLetters, 43:5649-5651 (2002).

Other methods for preparing boronic acids and boronic acid esters isdescribed in O. Baudoin, et al., J. Org. Chem., 65:9268-9271 (2000),wherein an aryl or heteroaryl halides or triflate are treated with adialkyloxyborane such as pinacolborane, in the presence of triethylamineand palladium (II) acetate in dioxane.

Alternatively, utilizing other coupling methods such as Stille coupling,compounds of formula (10), can be converted into the compound of formula(11) and (12) by treatment with organostannanes of formula(R_(y))₃SnR_(x) wherein R_(y) is alkyl or aryl, and R_(x) is aryl,heteroaryl, heterocyclyl, alkyl or alkenyl, or cycloalkyl, in thepresence of a palladium source such astris(dibenzylidineacetone)dipalladium (CAS # 52409-22-0) or palladiumdiacetate (CAS # 3375-31-3), and a ligand such as tri(2-furyl)phosphine(CAS # 5518-52-5) or triphenylarsine (CAS # 603-32-7). The reaction canbe performed in a solvent such as DMF at a temperature from about 25° C.to about 150° C. Such methods are described, for instance, in J. K.Stille Angew. Chem. Int. Ed. 25:508 (1986) and T. N. Mitchell,Synthesis, 803 (1992).

While many stannanes are commercially available or described in theliterature, it is also possible to prepare new stannanes fromarylhalides, aryltriflates, heteroarylhalides, and heteroaryltriflatesby reaction with hexa-alkyl distannanes of formula ((R_(x))₃Sn)₂ whereinR_(x) is alkyl or aryl, with aryl, heteroaryl, or heterocyclic halidesand triflates in the presence of a palladium source like Pd(Ph₃P)₄.Example of hexa-alkyl distannanes include, but not limited to,hexamethyldistannane (CAS # 661-69-8). Such methods are described, forinstance in Krische, et. al., Helvetica Chimica Acta 81(11):1909-1920(1998), and in Benaglia, et al., Tetrahedron Letters 38:4737-4740(1997). Alternatively, aryl, heteroaryl, or heterocyclic organolithiumand magnesium reagents can be treated with Bu₃SnCl to provide Stillereagents. These reagents can be reacted with compounds of formula (10)to provide compounds of formula (11) and (12) under Stille conditions. Areference describing the Stille reaction is A. F. Littke et al., J.Amer. Chem. Soc. 124:6343-6348 (2002).

Compounds of formulas (11) wherein m, R_(3a), R_(3b), R₄, and R₅ are asdefined in formula (I), alkylthio, and R₁ is —L₂—R₆, wherein L₂ is abond, and R₆ is a nitrogen-containing heterocyclic ring linked to theparent moiety through the nitrogen, may be prepared as follows. Thetreatment of a compound of formulas (10) wherein X₁ is I, Br or Cl, witha heterocycle of formula H—R₆, wherein H is a hydrogen on the nitrogenatom contained in the heterocycle, in the presence of a base such as,but not limited to, sodium t-butoxide or cesium carbonate, a metalcatalyst such as, but not limited to copper metal or CuI, palladiumdiacetate, and optionally with a ligand such as, but not limited to,BINAP or tri-tertbutylphosphine will provide compounds of formula (11).Similarly, the treatment of compounds of formula (10) wherein m, R_(3a),R_(3b), R₄, and R₅ are as defined in formula (I), and X₂ is I, Br or Clwith a heterocycle of formula H—R₆, wherein H is a hydrogen on thenitrogen atom contained in the heteroaryl or heterocycle using the sameconditions will provide compounds of formula (12). These reactions aretypically conducted in a solvent such as, but not limited to, dioxane,toluene or pyridine. References that describe these methods may be foundin the following: J. Hartwig et al., Angew. Chem. Int. Ed. 37:2046-2067(1998); J. P. Wolfe et al., Acc. Chem. Res., 13:805-818 (1998); M.Sugahara et al., Chem. Pharm. Bull., 45:719-721 (1997); J. P. Wolfe etal., J. Org. Chem., 65:1158-1174 (2000); F. Y. Kwong et al., Org. Lett.,4:581-584 (2002); A. Klapars et al., J. Amer. Chem. Soc., 123:7727-7729(2001); B. H. Yang et al., J. Organomet. Chem., 576:125-146 (1999); andA. Kiyomori et al., Tet. Lett., 40:2657-2640 (1999).

Compounds of formulas (11) wherein m, R₃, R_(3a), R_(3b), R₄, and R₅ areas defined in formula (I), and R₁ is —L₂—R₆, wherein L₂ is —NH— or—N(alkyl)-, and R₆ is as defined for a compound of formula (I) can beprepared as follows. The treatment of compounds of formula (10) whereinX₁ is I, Br or Cl with a compound of formula H₂N—R₆ or HN(alkyl)-R₆ anda base such as, but not limited to, sodium t-butoxide or cesiumcarbonate in the presence of a metal catalyst such as, but not limitedto, copper metal or CuI, palladium diacetate, and also optionally with aligand such as, but not limited to, BINAP, or tri-tert-butylphosphineunder heated conditions will provide compounds of formula (11).Similarly, compounds of formulas (12) wherein m, R₃, R_(3a), R_(3b), R₄,and R₅ are as defined in formula (I), and R₂ is —L₂—R₆, wherein L₂ is—NH— or —N(alkyl)-, and R₆ is as defined for a compound of formula (I)can be prepared by heating compounds of formula (10) wherein X₂ is I, Bror Cl with a compound of formula H₂N—R₆ or HN(alkyl)-R₆ utilizing thesame conditions. The reaction can be performed in a solvent such asdioxane, toluene, or pyridine. References that describe thesemethodologies may be found in the following: J. Hartwig, et al., Angew.Chem. Int. Ed., 37:2046-2067 (1998); J. P. Wolfe et al., Acc. Chem.Res., 13:805-818 (1998); J. P. Wolfe et al., J. Org. Chem., 65:1158-1174(2000); F. Y. Kwong et al., Org. Lett., 4:581-584 (2002); and B. H. Yanget al., J. Organomet. Chem., 576:125-146 (1999).

Compounds of formulas (11) wherein m, R₃, R_(3a), R_(3b), R₄ and R₅ areas defined in formula (I), and R₁ is L₂—R₆, wherein L₂ is oxygen and R₆is as defined in formula (I) can be prepared as follows. The treatmentof compounds of formula (10) wherein X₁ is I, Br or Cl, with a compoundof formula HO—R₆ using a base such as, but not limited to, sodiumhydride in a solvent such as toluene or N,N-dimethylformamide, in thepresence of a metal containing catalyst such as CuI or palladiumdiacetate under heated conditions will provide compounds of formula(11). Similarly, compounds of formulas (12) wherein m, R₃, R_(3a),R_(3b), R₄ and R₅ are as defined in formula (I), and R₂ is L₂—R₆,wherein L₂ is oxygen and R₆ is as defined in formula (I) can be preparedby heating compounds of formula (10) wherein X₂ is I, Br or Cl with acompound of formula HO—R₆ utilizing the same conditions. References thatdescribe these methodologies may be found in the following: J. Hartwiget al., Angew. Chem. Int. Ed., 37:2046-2067 (1998); K. E. Torraca etal., J. Amer. Chem. Soc., 123:10770-10771 (2001); S. Kuwabe et al., J.Amer. Chem. Soc., 123:12202-12206 (2001); K. E. Toracca et al., J. Am.Chem. Soc., 122:12907-12908 (2000); R. Olivera et al., Tet. Lett.,41:4353-4356 (2000); J.-F. Marcoux et al., J. Am. Chem. Soc.,119:10539-10540 (1997); A. Aranyos et al., J. Amer. Chem. Soc.,121:4369-4378 (1999); T. Satoh et al., Bull. Chem. Soc. Jpn.,71:2239-2246 (1998); J. F. Hartwig, Tetrahedron Lett., 38:2239-2246(1997); M. Palucki et al., J. Amer. Chem. Soc., 119:3395-3396 (1997); N.Haga et al, J. Org. Chem., 61:735-745 (1996); R. Bates et al., J. Org.Chem., 47:4374-4376 (1982); T. Yamamoto et al., Can. J. Chem., 61:86-91(1983); A. Aranyos et al., J. Amer. Chem. Soc., 121:4369-4378 (1999);and E. Baston et al., Synth. Commun., 28:2725-2730 (1998).

Compounds of formulas (11) wherein m, R₃, R_(3a), R_(3b), R₄ and R₅ areas defined in formula (I), and R₁ is L₂—R₆, wherein L₂ is sulfur and R₆is as defined for a compound of formula (I) can be prepared by heatingcompounds of formula (10) wherein X₁ is I, Br or Cl, with a compound offormula HS—R₆ in the presence of a base, with or without a metalcatalyst such as CuI or palladium diacetate, in a solvent such asdimethylformamide or toluene. Similarly, compounds of formula (12)wherein m, R₃, R_(3a), R_(3b), R₄ and R₅ are as defined in formula (I),and R₂ is L₂—R₆, wherein L₂ is sulfur and R₆ is as defined in formula(I) can be prepared by heating compounds of formula (10) wherein X₂ isI, Br or Cl with a compound of formula HS—R₆ utilizing the sameconditions. References that describe these methodologies may be found inthe following: G. Y. Li et al., J. Org. Chem., 66:8677-8681 (2001); Y.Wang et al., Bioorg. Med. Chem. Lett., 11:891-894 (2001); G. Liu et al.,J. Med. Chem., 44:1202-1210 (2001); G. Y. Li et al., Angew. Chem. Int.Ed., 40:1513-1516 (2001); U. Schopfer et al., Tetrahedron, 57:3069-3074(2001); and C. Palomo et al., Tet. Lett., 41:1283-1286 (2000); A. Pelteret al., Tet. Lett., 42:8391-8394 (2001); W. Lee et al., J. Org. Chem.,66:474-480 (2001); and A. Toshimitsu et al., Het. Chem., 12:392-397(2001).

As shown in Scheme 3, compounds of formula (13) when treated with anamine of formula R₄R₅NH followed by treatment with either sodiumcyanoborohydride in methanol, sodium triacetoxyborohydride indichloromethane, or borane-pyridine complex in a mixture of solventssuch as but not limited to dichloromethane and ethanol will providecompounds of formula (14). Compounds of formula (14) wherein m, R_(3a),R_(3b), R₄ and R₅ are as defined in Formula (I), R₂ is selected from thegroup consisting of hydrogen, alkoxy, halogen, cyano, or alkylthio, andX₁ is I, Br or Cl may be treated according to the conditions describingthe conversion of compounds of formula (10) into compounds of formula(11), to obtain compounds of formula (15). Similarly, compounds offormula (14), wherein, R_(3a), R_(3b), R₄ and R₅ are as defined inFormula (I), R₁ is selected from the group consisting of hydrogen,alkoxy, halogen, cyano, or alkylthio, and X₂ is I, Br or Cl may betreated according to the conditions describing the conversion ofcompounds of formula (10) into compounds of formula (12), to obtaincompounds of formula (16).

Scheme 4 shows an alternative route to the generation of compounds offormula (11) from compounds of formula (9), wherein m, R_(3a), R_(3b),R₄ and R₅ are as defined in Formula (I), and X₁ is I, Br or Cl.Treatment of (9) with a boronic acid or ester and palladium under Suzukiconditions will provide compounds of formula (18). The treatment ofcompounds of formula (18) with triflic anhydride and a base such as, butnot limited to, potassium carbonate in dichloromethane, followed bytreatment with an amine of formula R₄R₅NH and a base such as, but notlimited to, potassium carbonate will produce compounds of formula (11).Similarly, compounds of formula (9) wherein m, R_(3a), R_(3b), R₄ and R₅are as defined in Formula (I), and X₂ is I, Br or Cl when treated with aboronic acid or ester and palladium under Suzuki reaction conditionswill provide compounds of formula (19). Compounds of formula (19) whentreated with triflic anhydride and a base such as but not limited topotassium carbonate in dichloromethane followed by treatment with anamine of formula R₄R₅NH and a base such as but not limited to potassiumcarbonate will produce compounds of formula (12).

As outlined in Scheme 5, compounds of formula (8) when treated with asolution containing the anion of diethyl isocyanomethylphosphonate(itself generated from the phosphonic ester reagents of formula (20) anda base such as but not limited to sodium hydroxide or sodium methoxide)will provide compounds of formula (21). The use of this reactionmethodology is described in Moskal, et al. Recl. Trav. Pay Chem B. vol.106(5), 137-141 (1987) and Yan, et al. J. Medical Chemistry vol. 37(16),2619-2622 (1994). The hydrolysis of compounds of formula (21) underacidic conditions will provide aldehydes of formula (22). The aldehydeof compounds of formula (22) when treated with an amine R₄R₅NH, whereinR₄ and R₅ are as defined in formula (I), followed by treatment withsodium cyanoborohydride in methanol, sodium triacetoxyborohydride indichloromethane, or borane-pyridine complex in a mixture ofdichloromethane and methanol will provided compounds of formula (23).The compounds of formula (23) when treated according to the conditionsin Scheme 2 describing the Suzuki reaction will provide compounds offormula (24) or (25) depending on the appropriate substitution of X₁ orX₂.

As outlined in Scheme 6, compounds of formula (26), wherein X is bromoor iodo and R₂, R_(3a) and R_(3b) are as defined in formula (I), whentreated with a compound of formula (27), wherein R₁ is either a group ofthe formula —L₂—R₆ or a group of the formula—L_(3a)—R_(6a)—L_(3b)—R_(6b), wherein L₂ and L_(3a) are a bond, R₆ andR_(6a) are heterocycle (wherein the heterocycle contains a reactivenitrogen such as pyridazin-3(2H)-one or pyridine-2(1H)-one) and L_(3b)and R_(6a) are defined in formula (I), in the presence of copper powder,copper iodide, potassium carbonate and pyridine under heated conditionswill provide compounds of formula (28). Compounds of formula (28) whensubjected to oxidative conditions such as but not limited to Dess-Martinperiodinane ([87413-09-0], Aldrich Chemical Company), Swern oxidation orJones oxidation as known to one skilled in the art, will providecompounds of formula (29). Compounds of formula (29) when treated withan amine of formula R₃R₄NH followed by the addition of sodiumcyanoborohydride will provide compounds of formula (30). Alternatively,reducing agents described in Scheme 3 for the conversion of compounds offormula (13) into compounds of formula (14) may also be used for thistransformation. Compounds of formula (29) when treated with sodiumborohydride or another appropriate reducing agent known to one skilledin the art will provide compounds of formula (31). Compounds of formula(31) when treated with trifluoromethanesulfonic anhydride (also known astriflic anhydride) in the presence of a base such as but not limited topotassium carbonate followed by the treatment with an amine of formulaR₃R₄NH will provide compounds of formula (32). Both compounds of formula(30) and (32) are representative of compounds of the present inventionbut contain different stereochemical configurations.

Cyclobutane nitrile compounds (4) are available by known routes or arecommercially available. For example, 3-methylene cyclobutanecarbonitrile(CAS number 15760-35-7) is commercially available from Maybridge Plc,Trevilleft, Tintagel, Cornwall, PL34 0HW, United Kingdom, and from RyanScientific, Inc., PO Box 845, Isle of Palms, S.C., 29451, USA.1-methyl-3-methylenecyclobutanecarbonitrile (CAS number 32082-16-9) isavailable through methods described in “Methods of preparing 2- and3-functionally substituted methylenecyclobutanes via the cycloadditionof allene with acrylic acid derivatives” by Men'shchikov, V. A.(Otkrytoe Aktsionernoe Obshchestvo “VserossiiskiiNauchno-Issledovatel'skii Institut Organicheskogo Sinteza”, Russia), andfound in Chemical Abstracts Number 137:310640; and Russian patentapplication RU 2000-103966. Synthesis of1-methyl-3-methylenecyclobutanecarbonitrile is also described in“Cyclobutane Carboxamide Inhibitors of Fungal Melanin: Biosynthesis andtheir Evaluation as Fungicides” Jennings, et al. Bioorganic & MedicinalChemistry 8 (2000) 897-907; this reference also describes the synthesisof 3-methylene-1 (trifluoromethyl)cyclobutanecarbonitrile, 1-chloro-3methylenecyclobutanecarbonitrile, and describes a general method ofsynthesis of 1-substituted analogs of (4).1-chloro-3-methylenecyclobutanecarbonitrile is also available by methodsdescribed in Bienfait, et al. Tetrahedron (1991), 47(38), 8167-76. Theconversion of chloro compounds such as1-chloro-3-methylenecyclobutanecarbonitrile to fluoro compounds such as1-fluoro-3-methylenecyclobutanecarbonitrile is well-known, for exampleby treatment with fluoride ion. Compounds (4) can be converted tocompounds (5) and to compounds of the invention of general formula (I)by the routes described in Schemes 1-5 and described herein.

Cyclobutane carboxylic acid compounds (5) are also available by knownroutes or are commercially available. For example,1-hydroxy-3-methylenecyclobutanecarboxylic acid is described in Della,et al. Journal of the American Chemical Society (1994), 116(14),6159-6166. Other compounds (5) have been described in Jennings, et al.Bioorganic & Medicinal Chemistry 8 (2000) 897-907, for example1-methyl-3-methylenecyclobutanecarboxylic acid and1-ethyl-3-methylenecyclobutanecarboxylic acid; this reference provides ageneral method for the conversion of the commercially available3-methylenecyclobutanecarboxylic acid (Chemical Abstracts number15760-35-7, available from Ryan Scientific, Inc., PO Box 845, Isle ofPalms, S.C., 29451, USA, and other sources) to a variety of1-substituted 3-methylenecyclobutanecarboxylic acids. In thistransformation, the 3-methylenecyclobutanecarboxylic acid isdeprotonated with a base such as lithium di-isopropyl amide or otherbase, in a solvent such as THF, followed by treatment with anelectrophilic reagent. Suitable electrophilic reagents are ethyl iodide,TosMIC (toluene methyl isocyanide), CNBr, and the like.

Esters of cyclobutane carboxylic acid compounds (5) are available byknown routes or are commercially available, and these may be hydrolyzedto the cyclobutane carboxylic acid compounds (5) under basic conditions(NaOH) or acid conditions (HCl). For example, cyclobutanecarboxylicacid, 1-cyano-3-methylene-, methyl ester (Chemical abstracts number116546-99-7) is available for hydrolysis to1-cyano-3-methylenecyclobutanecarboxylic acid.

2-aminobenzenethiol compounds of formula (2) are available from avariety of routes or are commercially available. Examples of compounds(2) include 2-amino-5-(dimethylamino)benzenethiol (Chemical Abstractsnumber 860766-72-9, see Zincke, Th.; Muller, Joh. Marburg, Ber. (1913),46, 775-86); Benzenethiol, 2-amino-5-chloro-3-methoxy-, hydrochloride(Chemical Abstracts number 859032-36-3, see Takahashi, Torizo;Shibasaki, Juichiro; Okada, Jutaro. Syntheses of heterocyclic compoundsof nitrogen. L. Yakugaku Zasshi (1951), 71, 41-4.); Herz, Richard;2-amino-5-(phenylamino)benzenethiol (Chemical Abstracts number858833-38-2; see Friedlaender, Paul. Aryl mercaptan derivatives. (1923),DE 491224); 4-amino-3-mercaptobenzonitrile (Chemical Abstracts numer802559-53-1, see Bogert, Marston T.; Husted, Helen G. Thiazoles. XVIII.Synthesis of 2-phenylbenzothiazole-5-carboxylic acid and derivatives.Journal of the American Chemical Society (1932), 54, 3394-7);2-amino-5-ethoxybenzenethiol (Chemical Abstracts number 785727-27-7, seeWilde, Richard G.; Billheimer, Jeffrey T.; Germain, Sandra J.; Gillies,Peter J.; Higley, C. Anne; Kezar, Hollis S., III; Maduskuie, Thomas P.;Shimshick, Edward S.; Wexler, Ruth R. Acyl CoA: cholesterolacyltransferase (ACAT) inhibitors: ureas bearing heterocyclic groupsbioisosteric for an imidazole. Bioorganic & Medicinal Chemistry Letters(1995), 5(2), 167-72); 2-amino-5-(piperidin-1-ylsulfonyl)benzenethiol(Chem. Abstracts number 749216-22-6, commercially available fromEnamine, 23 Alexandra Matrosova Street, Kiev, 01103);3-amino-4-mercapto-benzoic acid methyl ester, described in Dannley, etal. Canadian J. Chem. vol. 43; (1965) 2610-2612);2-amino-5-benzyloxy-benzenethiol, described in Sugano, et al., Bioorg.Med. Chem. Lett. vol. 6 (1996), pp. 361-366.

Additionally, 2-aminobenzenethiol compounds of formula (2) are availableby basic hydrolysis of benzo[d]thiazol-2(3H)-ones, as described inExample 1a, or acid hydrolysis. A wide variety ofbenzo[d]thiazol-2(3H)-ones have been described, and methods ofpreparation are known to those skilled in the art of organic synthesis.Examples of general methods of preparation of benzo[d]thiazol-2(3H)-onesfrom anilines (which are themselves widely available commercially) canbe found in “Development of a Manufacturing Process for SibenadetHydrochloride, the Active Ingredient of Viozan” Giles, et al. OrganicProcess Research & Development, vol. 8(4), 628-642 (2004), and“Synthesis and Evaluation of Non-Catechol D-1 and D-2 Dopamine ReceptorAgonists: Benzimidazol-2-one, Benzoxazol-2-one, and the Highly PotentBenzothiazol-2-one 7-Ethylamines” Weinstock, et al., Journal ofMedicinal Chemistry (1987), 30, pp 1166-1176.

The compounds and intermediates of the invention may be isolated andpurified by methods well-known to those skilled in the art of organicsynthesis. Examples of conventional methods for isolating and purifyingcompounds can include, but are not limited to, chromatography on solidsupports such as silica gel, alumina, or silica derivatized withalkylsilane groups, by recrystallization at high or low temperature withan optional pretreatment with activated carbon, thin-layerchromatography, distillation at various pressures, sublimation undervacuum, and trituration, as described for instance in “Vogel's Textbookof Practical Organic Chemistry”, 5th edition (1989), by Furniss,Hannaford, Smith, and Tatchell, pub. Longman Scientific & Technical,Essex CM20 2JE, England.

The compounds of the invention have at least one basic nitrogen wherebythe compound can be treated with an acid to form a desired salt. Forexample, a compound may be reacted with an acid at or above roomtemperature to provide the desired salt, which is deposited, andcollected by filtration after cooling. Examples of acids suitable forthe reaction include, but are not limited to tartaric acid, lactic acid,succinic acid, as well as mandelic, atrolactic, methanesulfonic,ethanesulfonic, toluenesulfonic, naphthalenesulfonic, benzensulfonic,carbonic, fumaric, maleic, gluconic, acetic, propionic, salicylic,hydrochloric, hydrobromic, phosphoric, sulfuric, citric, orhydroxybutyric acid, camphorsulfonic, malic, phenylacetic, aspartic,glutamic, and the like.

Compositions of the Invention

The invention also provides pharmaceutical compositions comprising atherapeutically effective amount of a compound of formula (I) incombination with a pharmaceutically acceptable carrier. The compositionscomprise compounds of the invention formulated together with one or morenon-toxic pharmaceutically acceptable carriers. The pharmaceuticalcompositions can be formulated for oral administration in solid orliquid form, for parenteral injection or for rectal administration.

The term “pharmaceutically acceptable carrier”, as used herein, means anon-toxic, inert solid, semi-solid or liquid filler, diluent,encapsulating material or formulation auxiliary of any type. Someexamples of materials which can serve as pharmaceutically acceptablecarriers are sugars such as lactose, glucose and sucrose; starches suchas corn starch and potato starch; cellulose and its derivatives such assodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; cocoa butter and suppositorywaxes; oils such as peanut oil, cottonseed oil, safflower oil, sesameoil, olive oil, corn oil and soybean oil; glycols; such a propyleneglycol; esters such as ethyl oleate and ethyl laurate; agar; bufferingagents such as magnesium hydroxide and aluminum hydroxide; alginic acid;pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol,and phosphate buffer solutions, as well as other non-toxic compatiblelubricants such as sodium lauryl sulfate and magnesium stearate, as wellas coloring agents, releasing agents, coating agents, sweetening,flavoring and perfuming agents, preservatives and antioxidants can alsobe present in the composition, according to the judgment of one skilledin the art of formulations.

The pharmaceutical compositions of this invention can be administered tohumans and other mammals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments or drops), bucally or as an oral or nasal spray. Theterm “parenterally”, as used herein, refers to modes of administrationwhich include intravenous, intramuscular, intraperitoneal, intrasternal,subcutaneous, intraarticular injection and infusion.

Pharmaceutical compositions for parenteral injection comprisepharmaceutically acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions or emulsions and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and nonaqueous carriers, diluents, solventsor vehicles include water, ethanol, polyols (propylene glycol,polyethylene glycol, glycerol, and the like, and suitable mixturesthereof), vegetable oils (such as olive oil) and injectable organicesters such as ethyl oleate, or suitable mixtures thereof. Suitablefluidity of the composition may be maintained, for example, by the useof a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersions, and by the use of surfactants.

These compositions may also contain adjuvants such as preservativeagents, wetting agents, emulsifying agents, and dispersing agents.Prevention of the action of microorganisms may be ensured by variousantibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, sorbic acid, and the like. It may also bedesirable to include isotonic agents, for example, sugars, sodiumchloride and the like. Prolonged absorption of the injectablepharmaceutical form may be brought about by the use of agents delayingabsorption, for example, aluminum monostearate and gelatin.

In some cases, in order to prolong the effect of a drug, it is oftendesirable to slow the absorption of the drug from subcutaneous orintramuscular injection. This may be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the drug then depends upon itsrate of dissolution which, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered drug form is accomplished by dissolving or suspending thedrug in an oil vehicle.

Suspensions, in addition to the active compounds, may contain suspendingagents, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar, tragacanth, and mixtures thereof.

If desired, and for more effective distribution, the compounds of theinvention can be incorporated into slow-release or targeted-deliverysystems such as polymer matrices, liposomes, and microspheres. They maybe sterilized, for example, by filtration through a bacteria-retainingfilter or by incorporation of sterilizing agents in the form of sterilesolid compositions, which may be dissolved in sterile water or someother sterile injectable medium immediately before use.

Injectable depot forms are made by forming microencapsulated matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide.Depending upon the ratio of drug to polymer and the nature of theparticular polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides). Depot injectable formulations also are prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium just prior to use.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic, parenterally acceptablediluent or solvent such as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, one or morecompounds of the invention is mixed with at least one inertpharmaceutically acceptable carrier such as sodium citrate or dicalciumphosphate and/or a) fillers or extenders such as starches, lactose,sucrose, glucose, mannitol, and salicylic acid; b) binders such ascarboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia; c) humectants such as glycerol; d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate; e) solutionretarding agents such as paraffin; f) absorption accelerators such asquaternary ammonium compounds; g) wetting agents such as cetyl alcoholand glycerol monostearate; h) absorbents such as kaolin and bentoniteclay; and i) lubricants such as talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate, andmixtures thereof. In the case of capsules, tablets and pills, the dosageform may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using lactose or milk sugar aswell as high molecular weight polyethylene glycols.

The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract in a delayedmanner. Examples of materials which can be useful for delaying releaseof the active agent can include polymeric substances and waxes.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating carriers such as cocoa butter,polyethylene glycol or a suppository wax which are solid at ambienttemperature but liquid at body temperature and therefore melt in therectum or vaginal cavity and release the active compound.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the active compounds, the liquid dosage formsmay contain inert diluents commonly used in the art such as, forexample, water or other solvents, solubilizing agents and emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, groundnut,corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, and perfuming agents.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. A desired compound ofthe invention is admixed under sterile conditions with apharmaceutically acceptable carrier and any needed preservatives orbuffers as may be required. Ophthalmic formulation, ear drops, eyeointments, powders and solutions are also contemplated as being withinthe scope of this invention.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, animal and vegetable fats, oils,waxes, paraffins, starch, tragacanth, cellulose derivatives,polyethylene glycols, silicones, bentonites, silicic acid, talc and zincoxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of thisinvention, lactose, talc, silicic acid, aluminum hydroxide, calciumsilicates and polyamide powder, or mixtures of these substances. Sprayscan additionally contain customary propellants such aschlorofluorohydrocarbons.

Compounds of the invention may also be administered in the form ofliposomes. As is known in the art, liposomes are generally derived fromphospholipids or other lipid substances. Liposomes are formed by mono-or multi-lamellar hydrated liquid crystals that are dispersed in anaqueous medium. Any non-toxic, physiologically acceptable andmetabolizable lipid capable of forming liposomes may be used. Thepresent compositions in liposome form may contain, in addition to thecompounds of the invention, stabilizers, preservatives, and the like.The preferred lipids are the natural and synthetic phospholipids andphosphatidylcholines (lecithins) used separately or together.

Methods to form liposomes are known in the art. See, for example,Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, NewYork, N.Y., (1976), p 33 et seq.

Dosage forms for topical administration of a compound of this inventioninclude powders, sprays, ointments and inhalants. The active compound ismixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives, buffers or propellants, which canbe required. Opthalmic formulations, eye ointments, powders andsolutions are contemplated as being within the scope of this invention.Aqueous liquid compositions comprising compounds of the invention alsoare contemplated.

The compounds of the invention can be used in the form ofpharmaceutically acceptable salts, esters, or amides derived frominorganic or organic acids. The term “pharmaceutically acceptable salts,esters and amides”, as used herein, refer to carboxylate salts, aminoacid addition salts, zwitterions, esters and amides of compounds offormula (I) which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response, and the like, arecommensurate with a reasonable benefit/risk ratio, and are effective fortheir intended use.

The term “pharmaceutically acceptable salt” refers to those salts whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response, and the like, and arecommensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well-known in the art. The salts can be prepared insitu during the final isolation and purification of the compounds of theinvention or separately by reacting a free base function with a suitableorganic acid.

Representative acid addition salts include, but are not limited toacetate, adipate, alginate, citrate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate,digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate,fumarate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethansulfonate (isethionate), lactate, maleate,methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate,pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, phosphate, glutamate,bicarbonate, p-toluenesulfonate and undecanoate. Preferred salts of thecompounds of the invention are the tartrate and hydrochloride salts.

Also, the basic nitrogen-containing groups can be quaternized with suchagents as lower alkyl halides such as methyl, ethyl, propyl, and butylchlorides, bromides and iodides; dialkyl sulfates such as dimethyl,diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl,lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkylhalides such as benzyl and phenethyl bromides and others. Water oroil-soluble or dispersible products are thereby obtained.

Examples of acids which can be employed to form pharmaceuticallyacceptable acid addition salts include such inorganic acids ashydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acidand such organic acids as oxalic acid, maleic acid, succinic acid, andcitric acid.

Basic addition salts can be prepared in situ during the final isolationand purification of compounds of this invention by reacting a carboxylicacid-containing moiety with a suitable base such as the hydroxide,carbonate or bicarbonate of a pharmaceutically acceptable metal cationor with ammonia or an organic primary, secondary or tertiary amine.Pharmaceutically acceptable salts include, but are not limited to,cations based on alkali metals or alkaline earth metals such as lithium,sodium, potassium, calcium, magnesium, and aluminum salts, and the like,and nontoxic quaternary ammonia and amine cations including ammonium,tetramethylammonium, tetraethylammonium, methylamine, dimethylamine,trimethylamine, triethylamine, diethylamine, ethylamine and the such as.Other representative organic amines useful for the formation of baseaddition salts include ethylenediamine, ethanolamine, diethanolamine,piperidine, and piperazine.

The term “pharmaceutically acceptable ester”, as used herein, refers toesters of compounds of the invention which hydrolyze in vivo and includethose that break down readily in the human body to leave the parentcompound or a salt thereof. Examples of pharmaceutically acceptable,non-toxic esters of the invention include C₁-to-C₆ alkyl esters andC₅-to-C₇ cycloalkyl esters, although C₁-to-C₄ alkyl esters arepreferred. Esters of the compounds of formula (I) may be preparedaccording to conventional methods. For example, such esters may beappended onto hydroxy groups by reaction of the compound that containsthe hydroxy group with acid and an alkylcarboxylic acid such as aceticacid, or with acid and an arylcarboxylic acid such as benzoic acid. Inthe case of compounds containing carboxylic acid groups, thepharmaceutically acceptable esters are prepared from compoundscontaining the carboxylic acid groups by reaction of the compound withbase such as triethylamine and an alkyl halide, alkyl trifilate, forexample with methyliodide, benzyl iodide, cyclopentyl iodide. They alsomay be prepared by reaction of the compound with an acid such ashydrochloric acid and an alkylcarboxylic acid such as acetic acid, orwith acid and an arylcarboxylic acid such as benzoic acid.

The term “pharmaceutically acceptable amide”, as used herein, refers tonon-toxic amides of the invention derived from ammonia, primary C₁-to-C₆alkyl amines and secondary C₁-to-C₆ dialkyl amines. In the case ofsecondary amines, the amine may also be in the form of a 5- or6-membered heterocycle containing one nitrogen atom. Amides derived fromammonia, C₁-to-C₃ alkyl primary amides and C₁-to-C₂ dialkyl secondaryamides are preferred. Amides of the compounds of formula (I) may beprepared according to conventional methods. Pharmaceutically acceptableamides are prepared from compounds containing primary or secondary aminegroups by reaction of the compound that contains the amino group with analkyl anhydride, aryl anhydride, acyl halide, or aryl halide. In thecase of compounds containing carboxylic acid groups, thepharmaceutically acceptable esters are prepared from compoundscontaining the carboxylic acid groups by reaction of the compound withbase such as triethylamine, a dehydrating agent such as dicyclohexylcarbodiimide or carbonyl diimidazole, and an alkyl amine, dialkylamine,for example with methylamine, diethylamine, piperidine. They also may beprepared by reaction of the compound with an acid such as sulfuric acidand an alkylcarboxylic acid such as acetic acid, or with acid and anarylcarboxylic acid such as benzoic acid under dehydrating conditions aswith molecular sieves added. The composition can contain a compound ofthe invention in the form of a pharmaceutically acceptable prodrug.

The term “pharmaceutically acceptable prodrug” or “prodrug”, as usedherein, represents those prodrugs of the compounds of the inventionwhich are, within the scope of sound medical judgment, suitable for usein contact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response, and the like, commensurate witha reasonable benefit/risk ratio, and effective for their intended use.Prodrugs of the invention may be rapidly transformed in vivo to a parentcompound of formula (I), for example, by hydrolysis in blood. A thoroughdiscussion is provided in T. Higuchi and V. Stella, Pro-drugs as NovelDelivery Systems, V. 14 of the A.C.S. Symposium Series, and in Edward B.Roche, ed., Bioreversible Carriers in Drug Design, AmericanPharmaceutical Association and Pergamon Press (1987), herebyincorporated by reference.

The invention contemplates pharmaceutically active compounds eitherchemically synthesized or formed by in vivo biotransformation tocompounds of formula (I).

Methods of the Invention

The compounds and compositions of the invention are useful for treatingand preventing certain diseases and disorders in humans and animals. Asan important consequence of the ability of the compounds of theinvention to modulate the effects of histamine-3 receptors in cells, thecompounds described in the invention can affect physiological processesin humans and animals. In this way, the compounds and compositionsdescribed in the invention are useful for treating and preventingdiseases and disorders modulated by histamine-3 receptors. Typically,treatment or prevention of such diseases and disorders can be effectedby selectively modulating the histamine-3 receptors in a mammal, byadministering a compound or composition of the invention, either aloneor in combination with another active agent as part of a therapeuticregimen.

The compounds of the invention, including but not limited to thosespecified in the examples, possess an affinity for the histamine-3receptors and therefore, the compounds of the invention may be usefulfor the treatment and prevention of diseases or conditions such asattention-deficit hyperactivity disorder (ADHD), deficits in attention,dementia, and diseases with deficits of memory, learning, schizophrenia,cognitive deficits of schizophrenia, cognitive deficits and dysfunctionin psychiatric disorders, Alzheimer's disease, mild cognitiveimpairment, epilepsy, seizures, allergic rhinitis, and asthma, motionsickness, dizziness, Meniere's disease, vestibular disorders, vertigo,obesity, diabetes, type II diabetes, Syndrome X, insulin resistancesyndrome, metabolic syndrome, pain, including neuropathic pain,neuropathy, sleep disorders, narcolepsy, pathological sleepiness, jetlag, drug abuse, mood alteration, bipolar disorder, depression,obsessive compulsive disorder, Tourette's syndrome, Parkinson's disease,and medullary thyroid carcinoma, melanoma, and polycystic ovarysyndrome. The ability of histamine-3 receptor modulators, andconsequently the compounds of the invention, to prevent or treat suchdisorders is demonstrated by examples found in the following references.

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat attention-deficithyperactivity disorder (ADHD), and deficits in attention, may bedemonstrated by Cowart, et al. J. Med. Chem. 2005, 48, 38-55; Fox, G.B., et al. “Pharmacological Properties of ABT-239: II.Neurophysiological Characterization and Broad Preclinical Efficacy inCognition and Schizophrenia of a Potent and Selective Histamine H₃Receptor Antagonist”, Journal of Pharmacology and ExperimentalTherapeutics (2005) 313, 176-190; “Effects of histamine H₃ receptorligands GT-2331 and ciproxifan in a repeated acquisition avoidanceresponse in the spontaneously hypertensive rat pup.” Fox, G. B., et al.Behavioural Brain Research (2002), 131(1,2), 151-161; Yates, et al. JPET(1999) 289, 1151-1159 “Identification and PharmacologicalCharacterization of a Series of New 1H-4-Substituted-Imidazoyl HistamineH₃ Receptor Ligands”; Ligneau, et al. Journal of Pharmacology andExperimental Therapeutics (1998), 287, 658-666; Tozer, M. Expert OpinionTherapeutic Patents (2000) 10, p. 1045; M. T. Halpern, “GT-2331” CurrentOpinion in Central and Peripheral Nervous System Investigational Drugs(1999) 1, pages 524-527; Shaywitz et al., Psychopharmacology, 82:73-77(1984); Dumery and Blozovski, Exp. Brain Res., 67:61-69 (1987); Tedfordet al., J. Pharmacol. Exp. Ther., 275:598-604 (1995); Tedford et al.,Soc. Neurosci. Abstr., 22:22 (1996); and Fox, et al., Behav. Brain Res.,131:151-161 (2002); Glase, S. A., et al. “Attention deficithyperactivity disorder: pathophysiology and design of new treatments.”Annual Reports in Medicinal Chemistry (2002), 37 11-20; Schweitzer, J.B., and Holcomb, H. H. “Drugs under investigation for attention-deficithyperactivity disorder” Current Opinion in Investigative Drugs (2002) 3,p. 1207.

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat dementia, anddiseases with deficits of memory and learning, may be demonstrated by“Two novel and selective nonimidazole H₃ receptor antagonists A-304121and A-317920: II. In vivo behavioral and neurophysiologicalcharacterization.” Fox, G. B., et al. Journal of pharmacology andexperimental therapeutics (2003 June), 305(3), 897-908; “Identificationof novel H₃ receptor (H₃R) antagonist with cognition enhancingproperties in rats.” Fox, G. B.; Inflammation Research (2003), 52(Suppl.1), S31-S32; Bernaerts, P., et al. “Histamine H₃ antagonist thioperamidedose-dependently enhances memory consolidation and reverses amnesiainduced by dizocilpine or scopolamine in a one-trial inhibitoryavoidance task in mice” Behavioural Brain Research 154 (2004) 211-219;Onodera, et al. Nauyn-Schmiedebergs' Arch. Pharmacol. (1998), 357,508-513; Prast, et al. Brain Research (1996) 734, 316-318; Chen, et al.Brain Research (1999) 839, 186-189 “Effects of histamine onMK-801-induced memory deficits in radial maze performance in rats”;Passani, et al. “Central histaminergic system and cognition”Neuroscience and Biobehavioral Reviews (2000) 24, p 107-113.

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat schizophrenia,cognitive deficits of schizophrenia, and cognitive deficits, may bedemonstrated by Fox, G. B., et al. “Pharmacological Properties ofABT-239: II. Neurophysiological Characterization and Broad PreclinicalEfficacy in Cognition and Schizophrenia of a Potent and SelectiveHistamine H₃ Receptor Antagonist”, Journal of Pharmacology andExperimental Therapeutics (2005) 313, 176-190 and by “Enhancement ofprepulse inhibition of startle in mice by the H₃ receptor antagoniststhioperamide and ciproxifan.” Browman, Kaitlin E., et al. BehaviouralBrain Research (2004), 153(1), 69-76; “H₃ receptor blockade bythioperamide enhances cognition in rats without inducing locomotorsensitization.”; Komater, V. A., et al. Psychopharmacology (Berlin,Germany) (2003), 167(4), 363-372; M Rodrigues, F P Jansen, R Leurs, HTimmerman and G D Prell “Interaction of clozapine with the histamine H₃receptor in rat brain” British Journal of Pharmacology (1995), 114(8),pp. 1523-1524; Passani, et al. “Central histaminergic system andcognition” Neuroscience and Biobehavioral Reviews (2000) 24, p 107-113;Morriset, S., et al. “Atypical Neuroleptics Enhance Histamine Turnoverin Brain Via 5-Hydroxytryptamine_(2A) Receptor Blockade” Journal ofPharmacology and Experimental Therapeutics (1999) 288, pages 590-596.

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat dysfunction inpsychiatric disorders, Alzheimer's disease, and mild cognitiveimpairment may be demonstrated by Meguro, et al. Pharmacology,Biochemistry and Behavior (1995) 50(3), 321-325; Esbenshade, T., et al.“Pharmacological and behavioral properties of A-349821, a selective andpotent human histamine H3 receptor antagonist” Biochemical Pharmacology68 (2004) 933-945; Huang, Y.-W., et al. “Effect of the histamineH3-antagonist clobenpropit on spatial memory deficits induced by MK-801as evaluated by radial maze in Sprague-Dawley rats” Behavioural BrainResearch 151 (2004) 287-293; Mazurkiewicz-Kwilecki and Nsonwah, Can. J.Physiol. Pharmacol. (1989) 67, p. 75-78; P. Panula, et al., Neuroscience(1997) 82, 993-997; Haas, et al., Behav. Brain Res. (1995) 66, p. 4144;De Almeida and Izquierdo, Arch. Int. Pharmacodyn. (1986), 283, p.193-198; Kamei et al., Psychopharmacology, (1990) 102, p. 312-318; Kameiand Sakata, Jpn. J. Pharmacol. (1991), 57, p. 437-482; Schwartz et al.,Psychopharmacology, The Fourth Generation of Progress. Bloom and Kupfer(eds). Raven Press, New York, (1995) 397; and Wada, et al., Trends inNeurosci. (1991) 14, p. 415.

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat epilepsy, andseizures, may be demonstrated by Harada, C., et al. “Inhibitory effectof iodophenpropit, a selective histamine H3 antagonist, on amygdaloidkindled seizures” Brain Research Bulletin (2004) 63 p, 143-146; as wellas by Yokoyama, et al., Eur. J. Pharmacol. (1993) 234, p. 129-133;Yokoyama, et al. European Journal of Pharmacology (1994) 260, p. 23;Yokoyama and Iinuma, CNS Drugs (1996) 5, p. 321; Vohora, Life Sciences(2000) 66, p. 297-301; Onodera et al., Prog. Neurobiol. (1994) 42, p.685; Chen, Z., et al. “Pharmacological effects of carcinine onhistaminergic neurons in the brain” British Journal of Pharmacology(2004) 143, 573-580; R. Leurs, R. C. Vollinga and H. Timmerman, “Themedicinal chemistry and therapeutic potential of ligands of thehistamine H₃ receptor”, Progress in Drug Research (1995) 45, p. 170-165;Leurs and Timmerman, Prog. Drug Res. (1992) 39, p. 127; H. Yokoyama andK. Iinuma, “Histamine and Seizures: Implications for the treatment ofepilepsy”, CNS Drugs, 5(5): 321-330 (1995); and K. Hurukami, H.Yokoyama, K. Onodera, K. Iinuma and T. Watanabe, “AQ-0145, A newlydeveloped histamine H₃ antagonist, decreased seizure susceptibility ofelectrically induced convulsions in mice”, Meth. Find. Exp. Clin.Pharmacol., 17(C):70-73 (1995); Yawata, et al. “Role of histaminergicneurons in development of epileptic seizures in EL mice” Molecular BrainResearch 132 (2004) 13-17.

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat allergic rhinitis,and asthma, may be demonstrated by McLeod, R. L., Mingo, G. G., Herczku,C., DeGennaro-Culver, F., Kreutner, W., Egan, R. W., Hey, J. A.,“Combined histamine H1 and H3 receptor blockade produces nasaldecongestion in an experimental model of nasal congestion” Am. J.Rhinol. (1999a) 13, p. 391-399; McLeod, Robbie L.; Egan, Robert W.;Cuss, Francis M.; Bolser, Donald C.; Hey, John A. (Allergy,Schering-Plough Research Institute, Kenilworth, N.J., USA.) Progress inRespiratory Research (2001), 31 (in New Drugs for Asthma, Allergy andCOPD), pp. 133-136; A. Delaunois A., et al., “Modulation ofacetylcholine, capsaicin and substance P effects by histamine H₃receptors in isolated perfused rabbit lungs,” European Journal ofPharmacology (1995) 277, p. 243-250; Dimitriadou, et al., “Functionalrelationship between mast cells and C-sensitive nerve fibres evidencedby histamine H₃-receptor modulation in rat lung and spleen,” ClinicalScience (1994), 87, p. 151-163.

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat motion sickness,dizziness, Meniere's disease, vestibular disorders, and vertigo, may bedemonstrated by Pan, et al. Methods and Findings in ClinicalPharmacology (1998), 20(9), 771-777; O'Neill, et al. Methods andFindings in Clinical Pharmacology (1999) 21(4), 285-289; and by R.Leurs, R. C. Vollinga and H. Timmerman, “The medicinal chemistry andtherapeutic potential of ligands of the histamine H₃ receptor,” Progressin Drug Research (1995), 45, p. 170-165, Lozada, et al. “Plasticity ofhistamine H₃ receptor expression and binding in the vestibular nucleiafter labyrinthectomy in rat” BioMedCentral Neuroscience 2004, 5:32.

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat obesity, diabetes,type II diabetes, Syndrome X, insulin resistance syndrome, and metabolicsyndrome, may be demonstrated by Hancock, A. A. “Antiobesity effects ofA-331440, a novel non-imidazole histamine H3 receptor antagonist”European Journal of Pharmacology (2004) 487, 183-197; Hancock, A. A., etal. “Histamine H₃ antagonists in models of obesity” Inflamm. res. (2004)53, Supplement 1 S47-S48; as well as by E. Itoh, M. Fujimiay, and A.Inui, “Thioperamide, A histamine H₃ receptor antagonist, powerfullysuppresses peptide YY-induced food intake in rats,” Biol. Psych. (1999)45(4), p. 475-481; S. I. Yates, et al., “Effects of a novel histamine H₃receptor antagonist, GT-2394, on food intake and weight gain inSprague-Dawley rats,” Abstracts, Society for Neuroscience, 102.10:219(November, 2000); and C. Bjenning, et al., “Peripherally administeredciproxifan elevates hypothalamic histamine levels and potently reducesfood intake in the Sprague Dawley rat,” Abstracts, International SendaiHistamine Symposium, Sendai, Japan, #P39 (November, 2000); Sakata T; etal. “Hypothalamic neuronal histamine modulates ad libitum feeding byrats.” Brain research (1990 Dec. 24), 537(1-2), 303-6.

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat pain, includingneuropathic pain and neuropathy, may be demonstrated by Malmberg-Aiello,Petra; Lamberti, Claudia; Ghelardini, Carla; Giotti, Alberto; Bartolini,Alessandro. British Journal of Pharmacology (1994), 111(4), 1269-1279;Hriscu, Anisoara; Gherase, Florenta; Pavelescu, M.; Hriscu, E.“Experimental evaluation of the analgesic efficacy of someantihistamines as proof of the histaminergic receptor involvement inpain.” Farmacia, (2001), 49(2), 23-30, 76.

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat sleep disorders,including narcolepsy and pathological sleepiness, and jet lag, may bedemonstrated by Barbier, A. J., et al. “Acute wake-promoting actions ofJNJ-5207852, a novel, diamine-based H₃ antagonist” British Journal ofPharmacology (2004) 1-13; Monti et al., Neuropsychopharmacology (1996)15, 31-35; Lin et al., Brain Res. (1990) 523, p. 325-330; Monti, et al.,Neuropsychopharmacology (1996) 15, p. 31-35; Ligneau, et al. Journal ofPharmacology and Experimental Therapeutics (1998), 287, 658-666; Sakai,et al., Life Sci. (1991) 48, p. 2397-2404; Mazurkiewicz-Kwilecki andNsonwah, Can. J. Physiol. Pharmacol., (1989) 67, p. 75-78; P. Panula, etal., Neuroscience (1998) 44, 465-481; Wada, et al., Trends inNeuroscience (1991) 14, p. 415; and Monti, et al., Eur. J. Pharmacol.(1991), 205, p. 283; Dvorak, C., et al. “4-Phenoxypiperidines: Potent,Conformationally Restricted, Non-Imidazole Histamine H₃ Antagonists”Journal of Medicinal Chemistry (2005) 48, 2229-2238.

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat drug abuse.Amphetamine is an abused stimulant in humans. It, and similar abuseddrugs stimulate locomotor activity in animals, and it has been foundthat the H₃ antagonist thioperamide suppresses the locomotor stimulationinduced by amphetamine; therefore H₃ antagonists are likely to be usefulfor treating drug abuse as may be demonstrated by Clapham J.; KilpatrickG. J. “Thioperamide, the selective histamine H₃ receptor antagonist,attenuates stimulant-induced locomotor activity in the mouse”, Europeanjournal of pharmacology (1994), 259(2), 107-14.

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat mood alteration,bipolar disorder, depression, obsessive compulsive disorder, andTourette's syndrome, may be demonstrated by Lamberti, et al. BritishJournal of Pharmacology (1998) 123, 1331-1336; Perez-Garcia C, et. al.,Psychopharmacology (Berlin) (1999) 142(2): 215-20.

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat Parkinson'sdisease (a disease wherein patients have deficits in ability to initiatemovements, and patients' brain have low dopamine levels) may bedemonstrated by Sánchez-Lemus, E., et al. “Histamine H₃ receptoractivation inhibits dopamine D₁ receptor-induced cAMP accumulation inrat striatal slices” Neuroscience Letters (2004) 364, p. 179-184; Sakai,et al., Life Sci. (1991) 48, 2397-2404; Fox, G. B., et al.“Pharmacological Properties of ABT-239: II. NeurophysiologicalCharacterization and Broad Preclinical Efficacy in Cognition andSchizophrenia of a Potent and Selective Histamine H₃ ReceptorAntagonist” Journal of Pharmacology and Experimental Therapeutics,313:176-190, 2005; Chen, Z., et al. “Pharmacological effects ofcarcinine on histaminergic neurons in the brain” British Journal ofPharmacology (2004) 143, 573-580.

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat medullary thyroidcarcinoma, melanoma, polycystic ovary syndrome, may be demonstrated byPolish Med. Sci. Mon. (1998) 4(5): 747; Adam Szelag, “Role of histamineH₃-receptors in the proliferation of neoplastic cells in vitro,” Med.Sci. Monitor (1998) 4(5): 747-755; and C. H. Fitzsimons, et al.,“Histamine receptors signalling in epidermal tumor cell lines with H-rasgene alterations,” Inflammation Res. (1998) 47 (Suppl 1):S50-S51.

Compounds of the invention are particularly useful for treating andpreventing a condition or disorder affecting memory or cognition, forexample Alzheimer's disease, attention-deficit hyperactivity disorder,schizophrenia, or the cognitive deficits of schizophrenia.

Actual dosage levels of active ingredients in the pharmaceuticalcompositions of this invention can be varied so as to obtain an amountof the active compound(s) that is effective to achieve the desiredtherapeutic response for a particular patient, compositions and mode ofadministration. The selected dosage level will depend upon the activityof the particular compound, the route of administration, the severity ofthe condition being treated and the condition and prior medical historyof the patient being treated. However, it is within the skill of the artto start doses of the compound at levels lower than required to achievethe desired therapeutic effect and to gradually increase the dosageuntil the desired effect is achieved.

When used in the above or other treatments, a therapeutically effectiveamount of one of the compounds of the invention can be employed in pureform or, where such forms exist, in pharmaceutically acceptable salt,ester, amide or prodrug form. Alternatively, the compound can beadministered as a pharmaceutical composition containing the compound ofinterest in combination with one or more pharmaceutically acceptablecarriers. The phrase “therapeutically effective amount” of the compoundof the invention means a sufficient amount of the compound to treatdisorders, at a reasonable benefit/risk ratio applicable to any medicaltreatment. It will be understood, however, that the total daily usage ofthe compounds and compositions of the invention will be decided by theattending physician within the scope of sound medical judgment. Thespecific therapeutically effective dose level for any particular patientwill depend upon a variety of factors including the disorder beingtreated and the severity of the disorder; activity of the specificcompound employed; the specific composition employed; the age, bodyweight, general health, sex and diet of the patient; the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed; andlike factors well known in the medical arts. For example, it is wellwithin the skill of the art to start doses of the compound at levelslower than required to achieve the desired therapeutic effect and togradually increase the dosage until the desired effect is achieved.

For treatment or prevention of disease, the total daily dose of thecompounds of this invention administered to a human or lower animal mayrange from about 0.0003 to about 30 mg/kg/day. For purposes of oraladministration, more preferable doses can be in the range of from about0.0003 to about 1 mg/kg/day. If desired, the effective daily dose can bedivided into multiple doses for purposes of administration;consequently, single dose compositions may contain such amounts orsubmultiples thereof to make up the daily dose.

Compounds and compositions of the invention also are useful asdiagnostic tools. The ability of PET (positron emitting tomography) andsPECT to probe the degree of receptor occupancy in humans and animals byendogenous ligands (such as histamine for the histamine H₃ receptor) ordrugs (such with a clinically used drug that affects brain histaminelevels) is widely recognized. This constitutes the use of PET as abiomarker to assess efficacy of pharmacological interventions withdrugs. The topic and use of positron-emitting ligands for these purposeshas been generally reviewed, for example in “PET ligands for assessingreceptor occupancy in vivo” Burns, et al. Annual Reports in MedicinalChemistry (2001), 36, 267-276; “Ligand-receptor interactions as studiedby PET: implications for drug development” by Jarmo Hietala, Annals ofMedicine (Helsinki) (1999), 31(6), 438-443; “Positron emissiontomography neuroreceptor imaging as a tool in drug discovery, researchand development” Burns, et al. Current Opinion in Chemical Biology(1999), 3(4), 388-394. The compounds of the invention, synthesized with¹¹C, ¹⁸F, or other positron-emitting isotopes are suitable ligand toolsfor PET; a number of positron-emitting reagents have been synthesized,are available, and are known to those skilled in the art. Especiallysuitable compounds of the invention for this use are those wherein a¹¹CH₃ group can be incorporated in by reaction with ¹¹CH₃I. Also,especially suitable compounds of the use are those wherein a ¹⁸F groupcan be incorporated into the compound by reaction with ¹⁸F-fluorideanion. The incorporation of ¹¹CH₃I can be carried out according to amethod such as that described in Example 51, substituting ¹¹CH₃I for the¹²CH₃I used in Example 51. In a like manner, other analogs, whereincompounds of formula (1), wherein R₆, R_(6a), or R_(6b) are pyrazol-4-ylor pyrazol-2-yl can be treated with base and ¹¹CH₃I to prepare ligandsfor use in PET studies. For incorporation of ¹⁸F into compounds orcompositions of the invention, compounds of formula (I), wherein R₄R₅Nis 4-hydroxypiperidine or 4-hydroxymethylpyrrolidine, can be treatedwith methanesulfonic anhydride or triflic anhydride and a base in aninert solvent such as dichloromethane, and the resulting compound (amethanesulfonate or triflate) can be treated with ¹⁸F-fluoride bymethods well known to skilled in the art of synthetic organic chemistryor medicinal chemistry. Among compounds of the invention that aresuitable for use as ligands for PET studies are ¹⁸F and ¹¹C isotopes ofcompounds of the invention, including, but not limited to

-   Trans-6-(1-(¹¹C)methyl-1H-pyrazol-4-yl)-2-(3-piperidin-1-ylcyclobutyl)-1,3-benzothiazole;-   Trans-2-{3-[(2S)-2-((¹⁸F)fluoromethyl)pyrrolidin-1-yl]cyclobutyl}-6-pyrimidin-5-yl-1,3-benzothiazole;-   Trans-2-{3-[(2S)-2-((¹⁸F)fluoromethyl)pyrrolidin-1-yl]cyclobutyl}-6-pyrimidin-5-yl-1,3-benzothiazole;-   Trans-2-[3-(4-(¹⁸F)fluoropiperidin-1-yl)cyclobutyl]-6-(2-methoxypyrimidin-5-yl)-1,3-benzothiazole;-   Trans-6-(2,6-dimethylpyridin-3-yl)-2-[3-(4-(¹⁸F)fluoropiperidin-1-yl)cyclobutyl]-1,3-benzothiazole;-   Trans-Methyl-{3-[6-(1-(¹¹C)methyl-1H-pyrazol-4-yl)-benzothiazol-2-yl]-cyclobutyl}-propyl-amine;-   Trans-6-(1-(¹¹C)Methyl-1H-pyrazol-4-yl)-2-[3-(2-methyl-pyrrolidin-1-yl)-cyclobutyl]-benzothiazole;-   Trans-2-[3-(4-(¹⁸F)Fluoro-piperidin-1-yl)-cyclobutyl]-6-(1-methyl-1H-pyrazol-4-yl)-benzothiazole;    and-   Trans-2-[3-(4-(Fluoro-piperidin-1-yl)-cyclobutyl]-6-(1-(¹¹C)methyl-1H-pyrazol-4-yl)-benzothiazole.

The compounds and processes of the invention will be better understoodby reference to the following examples, which are intended as anillustration of and not a limitation upon the scope of the invention.

REFERENCE EXAMPLES Reference Example 1 3-methylenecyclobutanecarboxylicacid

3-Methylenecyclobutanecarbonitrile (CAS# 15760-35-7, 33.84 g, 0.368mole), sodium hydroxide (38 g, 0.95 mole) and water (50 mL) were mixedand heated at 110° C. for 30 min to give a two-phase mixture.Tetrabutylammonium hydroxide (40 wt. % in water, 0.7 mL) was added andthe organic phase became brown. Within 10 minutes, gas was evolved, andthe two phases became well mixed to give a light brown homogeneoussolution. Heating was continued at 110° C. for two days. The mixture wascooled to room temperature and then to 0° C. Concentrated hydrochloricacid (95 mL) was added very slowly to adjust the pH to 0.5-1.0. A whiteslurry was formed, which was extracted with ether (500 mL×2). Theorganic layer was dried (over Na₂SO₄), and concentrated to give an oil.This oil was distilled and collected at 108° C.-110° C. to give acolorless liquid (27.74 g, 68% yield). 1H NMR (300 MHz, CDCl₃) δ ppm4.77-4.88 (m, 2H), 3.10-3.24 (m, 1H), 2.86-3.09 (m, 4H).

Reference Example 2 3-methylenecyclobutanecarboxylic acid chloride

In a 50 mL round-bottom flask equipped with a dropping funnel and watercondenser with drying tube, the carboxylic acid prepared above (26.19 g,0.234 mole) was charged. Thionyl chloride (20.5 mL, 0.281 mole, 1.2equiv) was added dropwise. The mixture was heated at reflux (oil bathtemperature 90° C.) for 3 h then cooled to room temperature. Thecondenser was replaced with a distillation head and the mixture wasdistilled under vacuum. A clear colorless liquid was collected at 43-45°C. (23 g, 75% yield). 1H NMR (300 MHz, CDCl₃) δ ppm 4.85-4.93 (m, 2H),3.50-3.63 (m, 1H), 2.95-3.19 (m, 4H).

EXAMPLES Example 1Trans-2-{3-[(2R)-2-methylpyrrolidin-1-yl]cyclobutyl}-6-pyrimidin-5-yl-1,3-benzothiazoleExample 1A 2-Amino-5-bromo-benzenethiol

6-Bromo-2-benzothiazolinone (4.65 g, 20.0 mmole) and sodium hydroxide(15.4 g, 0.385 mole) were mixed in 40 ml water. The mixture was stirredat room temperature for 30 minutes to form a slurry, was then heated at100° C. and became a clear solution. The mixture continued to stir at100° C. overnight after which it was cooled to room temperature. Whilecooling in an ice bath, the pH of the solution was adjusted to 6 withacetic acid (22 ml). The resulting solid was collected by filtration,washed three times (3×) with water and dried under vacuum to give 4.60 gof title compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 7.23 (s, 1H), 6.98(d, J=7.80 Hz, 1H), 6.59 (d, J=8.82 Hz, 1H), 5.41 (br, 2H). MS:(M+H)⁺=203/205, (M+H)⁺=406.

Example 1B 6-Bromo-2-(3-methylene-cyclobutyl)-benzothiazole

The product of Example 1A (1.0 g, 4.90 mmole) was weighed into a 100 mlround bottom flask and pyrridium p-toluenesulfonate (0.37 g, 1.47 mmole)was added. The flask was placed on high vacuum overnight. Para-xylene(50 ml) was added followed by tiethylamine (0.68 ml, 4.9 mmole). Themixture was rapidly stirred at 50° C. to give an almost clear solution.A solution of 3-methylene-cyclobutanecarbonyl chloride (0.64 g, 4.9mmole) (prepared according to literature procedure, JACS, 1959, 81,2723-2728) in 10 ml xylene was then added dropwise over 15 minutes. Thetemperature was raised to 140° C. for 7 hours. The mixture was cooled toroom temperature, followed by the addition of ethyl acetate (100 ml).The resulting solution was washed with saturated sodium bicarbonate, andthe organic layer was dried (Na₂SO₄), and concentrated to give an oil.The crude product was purified by chromatography (20% hexane indichloromethane) to give the title compound (1.03 g, 75%). ¹H NMR (300MHz, CDCl₃) δ ppm 7.98 (d, J=2.03 Hz, 1H), 7.83 (d, J=8.82 Hz, 1H), 7.55(dd, J=8.82, 2.03 Hz, 1H), 4.83-4.98 (m, 2H), 3.83-4.04 (m, 1H),3.10-3.35 (m, 4H). MS: (M+H)⁺=279/281.

Example 1C 3-(6-Bromo-benzothiazol-2-yl)-cyclobutanone

The product of Example 1B (931 mg, 3.33 mmole) and osmium tetraoxide (28mg, cat.) were dissolved in 30 ml THF and 15 ml water. The solution wascooled to 0° C. Sodium periodate (1.5 g, 7.0 mmole) was added in smallportions. The mixture was stirred at room temperature overnight. Thesolution was quenched with water, and extracted three times withdichloromethane. The combined organics were dried over sodium sulfateand concentrated to give the crude product, which was purified bychromatography (20% hexane in dichloromethane) to give the titlecompound (710 mg, 76%). ¹H NMR (500 MHz, CDCl₃) δ ppm 8.00 (d, J=1.87Hz, 1H), 7.84 (d, J=8.74 Hz, 1H), 7.59 (dd, J=8.73, 1.87 Hz, 1H),3.96-4.10 (m, 1H), 3.54-3.76 (m, 4H). MS: (M+H)⁺=281/283

Example 1D Cis-3-(6-Bromo-benzothiazol-2-yl)-cyclobutanol

The product of Example 1C (710 mg, 2.52 mmole) was dissolved in 50 mlanhydrous THF and cooled to 0° C. L-selectride (1.0M in THF, 3.02 ml,3.02 mmole) was added slowly. The mixture was stirred at 0° C. for 10minutes, then warmed to room temperature for 30 minutes. It was thenquenched with 1 N sodium hydroxide (20 ml) and extracted three timeswith ethyl acetate. The organics were combined, dried over sodiumsulfate and concentrated to give the crude product, which was used inthe next step without further purification.

Example 1ETrans-6-bromo-2-{3-[(2R)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazole

The product of Example 1D (2.52 mmole) was dissolved in anhydrousdichloromethane (20 ml). Potassium carbonate (696 mg, 5.04 mmole) wasadded followed by trifluoromethanesulfonic anhydride (551 μl, 3.27mmole). The mixture was allowed to stir at room temperature for 2 hours,then another portion of potassium carbonate (1.74 g, 12.6 mmole) wasadded, followed by 2-(R)-methylpyrrolidine L-tartrate (preparedaccording to the procedure that described in: R. Altenbach et al., WO2004043458, and Y. Pu et al., Organic Process Research & Development,9(1), 45-50, 2005) (1.18 g, 5.04 mmole). The resulting mixture wasstirred at room temperature overnight. It was then quenched with water,and extracted three times with dichloromethane. The organic layers werecombined, washed with brine, dried over sodium sulfate, andconcentrated. The crude product was purified by column chromatography(0.5% ammonium hydroxide and 5% methanol in dichloromethane) to give 394mg (45%) of title compound. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.97 (d,J=1.84 Hz, 1H), 7.83 (d, J=8.90 Hz, 1H), 7.55 (dd, J=8.75, 1.99 Hz, 1H),3.75-3.88 (m, 1H), 3.40-3.56 (m, 1H), 3.00-3.10 (m, 1H), 2.61-2.79 (m,3H), 2.42-2.57 (m, 2H), 2.23-2.37 (m, 1H), 1.88-2.02 (m, 1H), 1.77-1.88(m, 1H), 1.61-1.76 (m, 1H), 1.39-1.54 (m, 1H), 1.11 (d, J=6.14 Hz, 3H).MS: (M+H)⁺=351/353.

Example 1FTrans-2-{3-[(2R)-2-methylpyrrolidin-1-yl]cyclobutyl}-6-pyrimidin-5-yl-1,3-benzothiazole

A solution of the product of Example 1E (40 mg, 0.114 mmole),pyrimidine-5-boronic acid (CAS # 109299-78-7) (21 mg, 0.169 mmole),dichlorobis(triphenylphosphine)palladium(II) (8 mg, 0.01 mmole) andpotassium carbonate (47 mg, 0.34 mmole) in 1 ml isopropanol was heatedat 85° C. overnight with stirring. The reaction was then quenched withwater and extracted three times with dichloromethane. The combinedorganic layers were washed with brine, dried over sodium sulfate,filtered, and concentrated. The crude product was purified by columnchromatography (eluted by 0.35% ammonium hydroxide and 3.5% methanol indichloromethane) to give 33 mg (82%/o yield) of title compound. ¹H NMR(400 MHz, CDCl₃) δ ppm 9.23 (s, 1H), 9.02 (s, 2H), 8.12 (d, J=8.59 Hz,1H), 8.06 (d, J=1.84 Hz, 1H), 7.67 (dd, J=8.44, 1.99 Hz, 1H), 3.83-3.94(m, 1H), 3.46-3.62 (m, 1H), 2.99-3.14 (m, 1H), 2.64-2.85 (m, 3H),2.43-2.64 (m, 2H), 2.23-2.40 (m, 1H), 1.89-2.03 (m, 1H), 1.78-1.91 (m,1H), 1.67-1.78 (m, 1H), 1.42-1.56 (m, 1H), 1.14 (d, J=4.91 Hz, 3H). MS:(M+H)⁺=351.

Example 2Trans-6-(2,6-dimethylpyridin-3-yl)-2-{3-[(2R)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazoleExample 2A2,6-Dimethyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine

A solution of 3-bromo-2,6-dimethylpyridine (5.10 g, 27.4 mmol) inanhydrous ether (160 ml) cooled to −78° C. under a nitrogen atmospherewas treated dropwise with n-butyl lithium (4.1 ml, 10 M in hexane) andstirred at −78° C. for 45 minutes.2-isopropoxy-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (10.2 g, 54.8mmol) in 20 ml of ether was added dropwise at −78° C. and stirred at−78° C. for 3 hours. The mixture was quenched with 10 ml of isopropanol,and allowed to warm to room temperature. 150 ml of saturated aqueousNaCl solution was added. The aqueous phase was separated and extractedwith dichloromethane (100 ml×6). The combined organic phases were driedand concentrated to provide the title compound as light brown oil (6.29g, 98.4%). ¹H NMR (300 MHz, CDCl₃) δ ppm 7.92 (d, J=7.46 Hz, 1H) 6.96(d, J=7.80 Hz, 1H) 2.73 (s, 3H) 2.53 (s, 3H) 1.34 (s, 12H). MS:(M+H)⁺=234.

Example 2BTrans-6-(2,6-dimethylpyridin-3-yl)-2-{3-[(2R)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazole

The title compound was prepared according to the procedure described inExample 1F, substituting the product of Example 2A forpyrimidine-5-boronic acid. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.02 (d, J=8.29Hz, 1H) 7.76 (d, J=1.84 Hz, 1H) 7.46 (d, J=7.67 Hz, 1H) 7.39 (dd,J=8.44, 1.69 Hz, 1H) 7.07 (d, J=7.67 Hz, 1H) 3.82-3.93 (m, 1H) 3.47-3.58(m, 1H) 2.98-3.13 (m, 1H) 2.64-2.84 (m, 3H) 2.59 (s, 3H) 2.50 (s, 3H)2.43-2.59 (m, 2H) 2.26-2.40 (m, 1H) 1.89-2.03 (m, 1H) 1.78-1.88 (m, 1H)1.61-1.75 (m, 1H) 1.40-1.54 (m, 1H) 1.13 (t, J=5.37 Hz, 3H). MS:(M+H)⁺=378.

Example 3Trans-6-(2,4-dimethoxypyrimidin-5-yl)-2-{3-[(2R)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazole

The title compound was prepared according to the procedure described inExample 1F, substituting 2,6-dimethoxy-5-pyrimidineboronic acid (CAS #89641-18-9) for pyrimidine-5-boronic acid. ¹H NMR (400 MHz, CDCl₃) δ ppm8.32 (s, 1H) 8.02 (d, J=8.59 Hz, 1H) 7.97 (d, J=1.84 Hz, 1H) 7.57 (dd,J=8.44, 1.69 Hz, 1H) 4.06 (s, 3H) 4.05 (s, 3H) 3.82-3.92 (m, 1H)3.45-3.59 (m, 1H) 3.02-3.13 (m, 1H) 2.65-2.82 (m, 3H) 2.47-2.62 (m, 2H)2.25-2.41 (m, 1H) 1.90-2.02 (m, 1H) 1.77-1.89 (m, 1H) 1.67-1.76 (m, 1H)1.53-1.66 (m, 1H) 1.14 (d, J=5.83 Hz, 3H). MS: (M+H)⁺=411.

Example 4Trans-6-(2-methoxypyrimidin-5-yl)-2-{3-[(2R)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazole

The title compound was prepared according to the procedure described inExample 1F, substituting 2-methoxypyrimidine-5-boronic acid (FrontierScientific, Inc., Logan, Utah, USA) for pyrimidine-5-boronic acid. ¹HNMR (500 MHz, CDCl₃) δ ppm 8.77 (s, 2H) 8.08 (d, J=8.42 Hz, 1H) 7.98 (d,J=1.56 Hz, 1H) 7.57 (dd, 1H) 4.09 (s, 3H) 3.83-3.95 (m, 1H) 3.50-3.62(m, 1H) 3.03-3.15 (m, 1H) 2.67-2.85 (m, 2H) 2.46-2.64 (m, 2H) 2.29-2.40(m, 1H) 1.92-2.03 (m, 1H) 1.82-1.89 (m, 1H) 1.65-1.79 (m, 1H) 1.44-1.63(m, 2H) 1.15 (s, 3H). MS: (M+H)⁺=381.

Example 5Trans-2-{3-[(2R)-2-methylpyrrolidin-1-yl]cyclobutyl}-6-pyridin-4-yl-1,3-benzothiazole

The title compound was prepared according to the procedure described inExample 1F, substituting pyridine-4-boronic acid forpyrimidine-5-boronic acid. ¹H NMR (500 MHz, CDCl₃) δ ppm 8.69 (d, J=6.24Hz, 2H) 8.12 (d, J=1.87 Hz, 1H) 8.08 (d, J=8.42 Hz, 1H) 7.73 (dd,J=8.42, 1.87 Hz, 1H) 7.56 (dd, J=4.52, 1.72 Hz, 2H) 3.85-3.93 (m, 1H)3.49-3.59 (m, 1H) 3.01-3.13 (m, 1H) 2.69-2.84 (m, 2H) 2.46-2.61 (m, 2H)2.28-2.42 (m, 1H) 1.92-2.01 (m, 1H) 1.79-1.88 (m, 1H) 1.69-1.78 (m, 1H)1.57-1.66 (m, 1H) 1.45-1.55 (m, 1H) 1.14 (d, J=5.62 Hz, 3H). MS:(M+H)⁺=350.

Example 6Trans-6-(6-methoxypyridin-3-yl)-2-{3-[(2R)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazole

The title compound was prepared according to the procedure described inExample 1F substituting 2-methoxypyridine-5-boronic acid forpyrimidine-5-boronic acid. ¹H NMR (300 MHz, CDCl₃) δ ppm 8.00 (d, J=8.48Hz, 1H) 7.87 (d, J=2.03 Hz, 1H) 7.67 (dd, J=9.15, 2.71 Hz, 1H) 7.56 (d,J=2.71 Hz, 1H) 7.49 (dd, J=8.48, 2.03 Hz, 1H) 6.70 (d, J=9.15 Hz, 1H)3.82-3.95 (m, 1H) 3.65 (s, 3H) 3.48-3.60 (m, 1H) 3.01-3.21 (m, 1H)2.65-2.87 (m, 2H) 2.45-2.64 (m, 2H) 2.28-2.44 (m, 1H) 1.92-2.05 (m, 1H)1.62-1.91 (m, 3H) 1.46-1.60 (m, 1H) 1.15 (s, 3H). MS: (M+H)⁺=380.

Example 7Trans-2-{3-[(2R)-2-methylpyrrolidin-1-yl]cyclobutyl}-6-pyridin-3-yl-1,3-benzothiazole

The title compound was prepared according to the procedure described inExample 1F, substituting pyridine-3-boronic acid forpyrimidine-5-boronic acid. ¹H NMR (300 MHz, CDCl₃) δ ppm 8.91 (d, J=1.70Hz, 1H) 8.62 (dd, J=4.92, 1.53 Hz, 1H) 8.02-8.15 (m, 2H) 7.89-7.97 (m,1H) 7.68 (dd, J=8.48, 1.70 Hz, 1H) 7.34-7.44 (m, 1H) 3.79-3.96 (m, 1H)3.46-3.62 (m, 1H) 3.02-3.16 (m, 1H) 2.65-2.88 (m, 2H) 2.47-2.63 (m, 2H)2.27-2.44 (m, 1H) 1.64-2.06 (m, 4H) 1.41-1.59 (m, 1H) 1.14 (t, J=6.95Hz, 3H). MS: (M+H)⁺=350.

Example 8Trans-3-(2-{3-[(2R)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazol-6-yl)quinoline

The title compound was prepared according to the procedure described inExample 1F, substituting3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline (CAS#171364-85-5) for pyrimidine-5-boronic acid. ¹H NMR (300 MHz, CDCl₃) δppm 9.24 (d, J=2.37 Hz, 1H) 8.37 (d, J=2.03 Hz, 1H) 8.08-8.23 (m, 3H)7.91 (d, J=7.46 Hz, 1H) 7.82 (dd, J=8.48, 1.70 Hz, 1H) 7.72-7.79 (m, 1H)7.61 (t, J=7.46 Hz, 1H) 3.87-4.00 (m, 1H) 3.46-3.64 (m, 1H) 3.01-3.15(m, 1H) 2.73-2.83 (m, 2H) 2.58-2.69 (m, 2H) 2.32-2.45 (m, 1H) 1.70-2.12(m, 5H) 1.55 (s, 3H). MS: (M+H)⁺=400.

Example 9Trans-6-(6-fluoropyridin-3-yl)-2-{3-[(2R)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazole

The title compound was prepared according to the procedure described inExample 1F, substituting2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine(available from Aldrich) for pyrimidine-5-boronic acid. ¹H NMR (300 MHz,CDCl₃) δ ppm 8.48 (d, J=2.71 Hz, 1H) 8.07 (d, J=8.48 Hz, 1H) 7.98-8.04(m, 2 H) 7.62 (dd, J=8.48, 2.03 Hz, 1H) 7.04 (dd, J=8.48, 2.71 Hz, 1H)3.84-3.97 (m, 1H) 3.46-3.68 (m, 1H) 2.95-3.22 (m, 1H) 2.68-2.87 (m, 2H)2.51-2.64 (m, 2H) 2.24-2.44 (m, 1H) 1.47-2.08 (m, 5H) 1.17 (s, 3H). MS:(M+H)⁺=368.

Example 10Trans-4-(2-{3-[(2R)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazol-6-yl)benzonitrile

The title compound was prepared according to the procedure described inExample 1F, substituting 4-cyanophenylboronic acid forpyrimidine-5-boronic acid. ¹H NMR (300 MHz, CDCl₃) δ ppm 8.05-8.06 (m,2H) 7.75 (s, 4H) 7.68 (dd, J=8.82, 1.70 Hz, 1H) 3.83-3.94 (m, 1H)3.46-3.58 (m, 1H) 3.01-3.15 (m, 1H) 2.65-2.86 (m, 2H) 2.45-2.63 (m, 2H)2.27-2.42 (m, 1H) 1.65-2.03 (m, 4H) 1.42-1.57 (m, 1H) 1.14 (d, J=6.10Hz, 3H). MS: (M+H)⁺=374.

Example 11Trans-2-{3-[(2S)-2-methylpyrrolidin-1-yl]cyclobutyl}-6-pyrimidin-5-yl-1,3-benzothiazoleExample 11ATrans-6-bromo-2-{3-[(2S)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazole

The title compound was prepared according to the procedure described inExample 1E, substituting 2-(S)-methylpyrrolidine for2-(R)-methylpyrrolidine. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.98 (d, J=1.87Hz, 1H) 7.82 (d, J=8.74 Hz, 1H) 7.56 (dd, J=8.73, 2.18 Hz, 1H) 3.87 (t,J=9.83 Hz, 1H) 3.65-3.80 (m, 1H) 3.22-3.39 (m, 1H) 2.82-3.00 (m, 3H)2.69-2.78 (m, 1H) 2.56-2.66 (m, 2H) 2.04-2.14 (m, 1H) 1.89-2.03 (m, 1H)1.78-1.89 (m, 1H) 1.61-1.72 (m, 1H) 1.27 (d, J=4.37 Hz, 3H). MS:(M+H)⁺=351/353.

Example 11BTrans-2-{3-[(2S)-2-methylpyrrolidin-1-yl]cyclobutyl}-6-pyrimidin-5-yl-1,3-benzothiazole

The title compound was prepared according to the procedure described inExample 1F, substituting Example 11A for Example 1E. ¹H NMR (500 MHz,CDCl₃) δ ppm 9.24 (s, 1H) 8.97-9.08 (s, 2H) 8.12 (d, J=8.54 Hz, 1H) 8.07(d, J=1.53 Hz, 1H) 7.67 (dd, J=8.54, 1.83 Hz, 1H) 3.86-3.96 (m, 1H)3.49-3.68 (m, 1H) 3.03-3.21 (m, 1H) 2.69-2.87 (m, 3H) 2.53-2.66 (m, 2H)2.26-2.44 (m, 1H) 1.94-2.08 (m, 1H) 1.80-1.94 (m, 1H) 1.68-1.81 (m, 1H)1.53-1.64 (m, 1H) 1.16 (s, 3H). MS: (M+H)⁺=351.

Example 12Trans-6-(2,4-dimethoxypyrimidin-5-yl)-2-{3-[(2S)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazole

The title compound was prepared according to the procedure described inExample 1F, substituting the product of Example 11A for the product ofExample 1E and substituting 2,6-dimethoxy-5-pyrimidineboronic acid forpyrimidine-5-boronic acid. ¹H NMR (500 MHz, CDCl₃) δ ppm 8.32 (s, 1H)8.02 (d, J=8.54 Hz, 1H) 7.98 (d, J=1.53 Hz, 1H) 7.57 (dd, J=8.39, 1.68Hz, 1H) 4.06 (s, 3H) 4.05 (s, 3H) 3.83-3.95 (m, 1H) 3.51-3.72 (m, 1H)3.10-3.29 (m, 1H) 2.68-2.80 (m, 3H) 2.40-2.65 (m, 3H) 1.49-2.13 (m, 4H)1.10-1.27 (s, 3H). MS: (M+H)⁺=411.

Example 13Trans-6-(2,6-dimethylpyridin-3-yl)-2-{3-[(2S)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazole

The title compound was prepared according to the procedure described inExample 1F, substituting the Example 11A for the Example 1E andsubstituting the product of Example 2A for pyrimidine-5-boronic acid. ¹HNMR (500 MHz, CDCl₃) δ ppm 8.02 (d, J=8.24 Hz, 1H) 7.77 (d, J=1.22 Hz,1H) 7.46 (d, J=7.63 Hz, 1H) 7.40 (dd, J=8.39, 1.68 Hz, 1H) 7.07 (d,J=7.63 Hz, 1H) 3.83-3.95 (m, 1H) 3.49-3.65 (m, 1H) 3.04-3.18 (m, 1H)2.69-2.83 (m, 3H) 2.59 (s, 3H) 2.53 (s, 3H) 2.39-2.63 (m, 3H) 1.95-2.03(m, 1H) 1.81-1.94 (m, 1H) 1.69-1.80 (m, 1H) 1.58-1.68 (m, 1H) 1.16 (s,3H). MS: (M+H)⁺=378.

Example 14Trans-6-(2-methoxypyrimidin-5-yl)-2-{3-[(2S)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazole

The title compound was prepared according to the procedure described inExample 1F, except for substituting the product of Example 11A for theproduct of Example 1E and substituting 2-methoxypyrimidine-5-boronicacid for pyrimidine-5-boronic acid. ¹H NMR (500 MHz, CDCl₃) δ ppm 8.77(s, 2H) 8.08 (d, J=8.42 Hz, 1H) 7.98 (d, J=1.87 Hz, 1H) 7.60 (dd,J=8.58, 1.72 Hz, 1H) 4.09 (s, 3H) 3.84-3.98 (m, 1H) 3.47-3.65 (m, 1H)2.99-3.18 (m, 1H) 2.66-2.80 (m, 2H) 2.44-2.62 (m, 2H) 2.27-2.44 (m, 1H)1.92-2.04 (m, 1H) 1.80-1.92 (m, 1H) 1.67-1.78 (m, 1H) 1.44-1.64 (m, 2H)1.14 (s, 3H). MS: (M+H)⁺=378.

Example 15Trans-6-(6-methoxypyridin-3-yl)-2-{3-[(2S)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazole

The title compound was prepared according to the procedure described inExample 1F, except for substituting the product of Example 11A for theproduct of Example 1E and substituting 6-methoxy-3-pyridineboronic acidfor pyrimidine-5-boronic acid. ¹H NMR (500 MHz, CDCl₃) δ ppm 8.43 (d,J=2.18 Hz, 1H) 8.03 (d, J=8.42 Hz, 1H) 7.97 (d, J=1.56 Hz, 1H) 7.83 (dd,J=8.58, 2.65 Hz, 1H) 7.61 (dd, J=8.42, 1.56 Hz, 1H) 6.84 (d, J=8.73 Hz,1H) 4.00 (s, 3H) 3.81-3.92 (m, 1H) 3.47-3.58 (m, 1H) 2.97-3.15 (m, 1H)2.66-2.85 (m, 2H) 2.44-2.64 (m, 2H) 2.26-2.39 (m, 1H) 1.92-2.03 (m, 1H)1.79-1.89 (m, 1H) 1.67-1.77 (m, 1H) 1.46-1.64 (m, 2H) 1.14 (d, J=5.30Hz, 3H). MS: (M+H)⁺=380.

Example 16Trans-3-(2-{3-[(2S)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazol-6-yl)quinoline

The title compound was prepared according to the procedure described inExample 1F, substituting the product of Example 11A for the product ofExample 1E and substituting3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline forpyrimidine-5-boronic acid. ¹H NMR (500 MHz, CDCl₃) δ ppm 9.24 (d, J=2.50Hz, 1H) 8.37 (d, J=2.50 Hz, 1H) 8.09-8.21 (m, 3H) 7.90 (d, J=8.11 Hz,1H) 7.81 (dd, J=8.42, 1.87 Hz, 1H) 7.71-7.78 (m, 1H) 7.54-7.66 (m, 1H)3.82-3.99 (m, 1H) 3.46-3.64 (m, 1H) 2.98-3.16 (m, 1H) 2.65-2.86 (m, 2H)2.42-2.64 (m, 2H) 2.28-2.41 (m, 1H) 1.92-2.05 (m, 1H) 1.81-1.89 (m, 1H)1.69-1.78 (m, 1H) 1.44-1.63 (m, 2H) 1.16 (s, 3H). MS: (M+H)⁺=400.

Example 17Cis-2-{3-[(2R)-2-methylpyrrolidin-1-yl]cyclobutyl}-6-pyrimidin-5-yl-1,3-benzothiazoleExample 17A Cis6-bromo-2-{3-[(2R)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazole

The product of Example 1C (500 mg, 1.77 mmole) was dissolved in 6 mldichloromethane and 4 ml ethanol. 2-(R)-methylpyrrolidine (1.04 g, 4.43mmole, toluene extract from 50% sodium hydroxide) was added and stirredat room temperature for 30 minutes. Then borane-pyridine (358 μl, 3.54mmole) was added. The mixture was stirred at room temperature overnight.The reaction was quenched with saturated sodium bicarbonate andextracted with dichloromethane. The combined organic layers were washedwith brine, dried over sodium sulfate, filtered, and concentrated underreduced pressure to give the crude product which was purified by columnchromatography (0.4% ammonium hydroxide and 4% methanol indichloromethane) to give 45 mg (9% yield) of the title compound. ¹H NMR(500 MHz, CDCl₃) δ ppm 7.98 (d, J=1.83 Hz, 1H) 7.80 (d, J=8.85 Hz, 1H)7.54 (dd, J=8.54, 1.83 Hz, 1H) 3.54-3.65 (m, 1H) 3.15-3.29 (m, 1H)3.00-3.13 (m, 1H) 2.73-2.86 (m, 1H) 2.56-2.69 (m, 2H) 2.32-2.57 (m, 3H)1.92-2.05 (m, 1H) 1.79-1.90 (m, 1H) 1.67-1.78 (m, 1H) 1.46-1.57 (m, 1H)1.17 (s, 3H). MS: (M+H)⁺=351/353.

Example 17BCis-2-{3-[(2R)-2-methylpyrrolidin-1-yl]cyclobutyl}-6-pyrimidin-5-yl-1,3-benzothiazole

The title compound was prepared according to the procedure described inExample 1F, substituting Example the product of 17A for the product ofExample 1E. ¹H NMR (400 MHz, CDCl₃) δ ppm 9.23 (s, 1H) 9.01 (s, 2H)8.03-8.13 (m, 2H) 7.65 (dd, J=8.44, 1.69 Hz, 1H) 3.57-3.74 (m, 1H)3.17-3.31 (m, 1H) 3.01-3.12 (m, 1H) 2.76-2.88 (m, 1H) 2.61-2.70 (m, 1H)2.44-2.59 (m, 3H) 2.30-2.40 (m, 1H) 1.91-2.05 (m, 1H) 1.78-1.89 (m, 1H)1.67-1.79 (m, 1H) 1.44-1.62 (m, 1H) 1.17 (s, 3H). MS: (M+H)⁺=351.

Example 18Cis-6-(2,6-dimethylpyridin-3-yl)-2-{3-[(2R)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazole

The title compound was prepared according to the procedure described inExample 1F, substituting the product of Example 17A for the product ofExample 1E and substituting the product of Example 2A forpyrimidine-5-boronic acid. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.99 (d, J=8.29Hz, 1H) 7.76 (d, J=1.84 Hz, 1H) 7.45 (d, J=7.67 Hz, 1H) 7.38 (dd,J=8.44, 1.69 Hz, 1H) 7.06 (d, J=7.36 Hz, 1H) 3.57-3.70 (m, 1H) 3.14-3.29(m, 1H) 2.99-3.13 (m, 1H) 2.73-2.85 (m, 1H) 2.59 (s, 3H) 2.49 (s, 3H)2.28-2.67 (m, 5H) 1.91-2.01 (m, 1H) 1.77-1.88 (m, 1H) 1.59-1.73 (m, 1H)1.43-1.53 (m, 1H) 1.15 (s, 3H). MS: (M+H)⁺=378.

Example 19Cis-2-{3-[(2S)-2-methylpyrrolidin-1-yl]cyclobutyl}-6-pyrimidin-5-yl-1,3-benzothiazoleExample 19ACis-6-bromo-2-{3-[(2S)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazole

The product of Example 1C (500 mg, 1.77 mmole) was dissolved in 6 mldichloromethane and 4 ml ethanol. 2-(S)-methylpyrrolidine (1.04 g, 4.43mmole, toluene extract from 50% sodium hydroxide) was then added and thesolution was stirred at room temperature for 30 minutes. Borane-pyridine(358 μl, 3.54 mmole) was added, and the mixture was stirred at roomtemperature overnight. The reaction was quenched with saturated sodiumbicarbonate and extracted three times with dichloromethane. The combinedorganic layers were washed with brine, dried over sodium sulfate,filtered, and concentrated to give the crude product which was purifiedby column chromatography (0.4% ammonium hydroxide and 4% methanol indichloromethane) to give 98 mg (16% yield) of the title compound. ¹H NMR(500 MHz, CDCl₃) δ ppm 7.98 (d, J=2.14 Hz, 1H) 7.80 (d, J=8.85 Hz, 1H)7.54 (dd, J=8.54, 1.83 Hz, 1H) 3.54-3.65 (m, 1H) 3.15-3.29 (m, 1H)3.00-3.12 (m, 1H) 2.74-2.85 (m, 1H) 2.58-2.68 (m, 1H) 2.43-2.56 (m, 3H)2.30-2.39 (m, 1H) 1.92-2.02 (m, 1H) 1.78-1.89 (m, 1H) 1.70-1.76 (m, 1H)1.44-1.59 (m, 1H) 1.16 (s, 3H). MS: (M+H)⁺=351/353.

Example 19BCis-2-{3-[(2S)-2-methylpyrrolidin-1-yl]cyclobutyl}-6-pyrimidin-5-yl-1,3-benzothiazole

The title compound was prepared according to the procedure described inExample 1F, substituting the product of Example 19A for the product ofExample 1E. ¹H NMR (400 MHz, CDCl₃) δ ppm 9.23 (s, 1H) 9.01 (s, 2H)8.00-8.13 (m, 2H) 7.65 (dd, J=8.44, 1.69 Hz, 1H) 3.58-3.75 (m, 1H)3.15-3.28 (m, 1H) 3.00-3.12 (m, 1H) 2.75-2.86 (m, 1H) 2.60-2.71 (m, 1H)2.43-2.58 (m, 3H) 2.30-2.42 (m, 1H) 1.91-2.05 (m, 1H) 1.76-1.90 (m, 1H)1.66-1.76 (m, 1H) 1.40-1.56 (m, 1H) 1.16 (s, 3H). MS: (M+H)⁺=351.

Example 20Cis-6-(2,4-dimethoxypyrimidin-5-yl)-2-{3-[(2S)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazole

The title compound was prepared according to the procedure described inExample 1F, substituting the product of Example 19A for the product ofExample 1E and substituting 2,6-dimethoxy-5-pyrimidineboronic acid forpyrimidine-5-boronic acid. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.31 (s, 1H)7.91-8.03 (m, 2H) 7.55 (dd, J=8.44, 1.69 Hz, 1H) 4.06 (s, 3H) 4.05 (s,3H) 3.55-3.70 (m, 1H) 3.15-3.29 (m, 1H) 3.02-3.14 (m, 1H) 2.72-2.88 (m,1H) 2.60-2.71 (m, 1H) 2.43-2.56 (m, 3H) 2.30-2.40 (m, 1H) 1.91-2.02 (m,1H) 1.79-1.88 (m, 1H) 1.66-1.77 (m, 1H) 1.44-1.55 (m, 1H) 1.16 (s, 3H).MS: (M+H)⁺=411.

Example 21Cis-6-(2,6-dimethylpyridin-3-yl)-2-{3-[(2S)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazole

The title compound was prepared according to the procedure described inExample 1F, substituting the product of Example 19A for the product ofExample 1E and substituting the product of Example 2A forpyrimidine-5-boronic acid. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.99 (d, J=8.29Hz, 1H) 7.76 (d, J=1.53 Hz, 1H) 7.45 (d, J=7.67 Hz, 1H) 7.38 (dd,J=8.44, 1.69 Hz, 1H) 7.06 (d, J=7.67 Hz, 1H) 3.58-3.70 (m, 1H) 3.16-3.30(m, 1H) 3.00-3.13 (m, 1H) 2.69-2.86 (m, 1H) 2.59-2.68 (m, 1H) 2.59 (s,3H) 2.49 (s, 3H) 2.42-2.52 (m, 3H) 1.91-2.03 (m, 1H) 1.78-1.87 (m, 1H)1.67-1.77 (m, 1H) 1.42-1.57 (m, 1H) 1.16 (s, 3H). MS: (M+H)⁺=378.

Example 22Trans-2-(2-{3-[(2R)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazol-6-yl)pyridazin-3(2H)-one

The product of Example 1E (30 mg, 0.085 mmole), 3(2H)-pyridazinone (CAS# 504-30-3) (16 mg, 0.17 mmole), copper (11 mg, 0.17 mmole), andpotassium carbonate (71 mg, 0.51 mmole) were mixed in degassed pyridine(1 ml) and the mixture was heated at reflux overnight. The reaction wasquenched with water and extracted three times with dichloromethane. Thecombined organic layers were washed with brine, dried over sodiumsulfate, filtered, and concentrated under reduced pressure to give thecrude product which was purified by column chromatography (0.35%ammonium hydroxide and 3.5% methanol in dichloromethane) to give 23 mg(74% yield) of title compound. ¹H NMR (500 MHz, CDCl₃) δ ppm 8.15 (m,1H) 8.05 (m, 1H) 7.92 (dd, J=3.74, 1.87 Hz, 1H) 7.69 (dd, J=8.73, 2.18Hz, 1H) 7.20-7.32 (m, 1H) 7.08 (dd, J=9.51, 1.72 Hz, 1H) 3.86-3.99 (m,1H) 3.58-3.70 (m, 1H) 3.15-3.27 (m, 1H) 3.01-3.13 (m, 1H) 2.74-2.87 (m,1H) 2.28-2.71 (m, 4H) 1.90-2.03 (m, 1H) 1.79-1.90 (m, 1H) 1.66-1.78 (m,1H) 1.44-1.65 (m, 1H) 1.16 (s, 3H) MS: (M+H)⁺=367.

Example 23Trans-6-methyl-2-(2-{3-[(2R-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazol-6-yl)pyridazin-3(2H)-one

The title compound was prepared according to the procedure described inExample 22, substituting 6-methyl-3(2H)-pyridazinone (CAS #13327-27-0)for 3(2H)-pyridazinone. ¹H NMR (500 MHz, CDCl₃) δ ppm 8.12 (d, J=1.87Hz, 1H) 8.01 (d, J=8.74 Hz, 1H) 7.68 (dd, J=8.73, 2.18 Hz, 1H) 7.16 (d,J=9.36 Hz, 1H) 7.00 (d, J=9.67 Hz, 1H) 3.55-3.70 (m, 1H) 3.15-3.25 (m,1H) 3.02-3.14 (m, 1H) 2.74-2.84 (m, 1H) 2.59-2.69 (m, 1H) 2.45-2.56 (m,2H) 2.40 (s, 3H) 2.30-2.37 (m, 1H) 1.91-2.02 (m, 1H) 1.78-1.87 (m, 1H)1.69-1.77 (m, 1H) 1.55-1.67 (m, 1H) 1.46-1.52 (m, 1H) 1.16 (d, J=1.87Hz, 3H). MS: (M+H)⁺=381.

Example 24Trans-5-methyl-1-(2-{3-[(2R)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazol-6-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure described inExample 22, substituting 5-methyl-2(1H)-pyridone (CAS #1003-68-5) for3(2H)-pyridazinone. ¹H NMR (500 MHz, CDCl₃) δ ppm 8.03 (m, 1H) 7.88 (d,J=1.87 Hz, 1H) 7.42 (dd, J=8.58, 2.03 Hz, 1H) 7.25-7.32 (m, 1H) 7.15 (s,1H) 6.62 (d, J=9.36 Hz, 1H) 3.57-3.69 (m, 1H) 3.15-3.25 (m, 1H)3.01-3.11 (m, 1H) 2.73-2.83 (m, 1H) 2.58-2.67 (m, 1H) 2.42-2.54 (m, 2H)2.31-2.39 (m, 1H) 2.12 (s, 3H) 1.91-2.03 (m, 1H) 1.78-1.89 (m, 1H)1.66-1.75 (m, 1H) 1.56-1.65 (m, 1H) 1.44-1.53 (m, 1H) 1.15 (d, J=4.06Hz, 3H). MS: (M+H)⁺=380.

Example 25Trans-3-methyl-1-(2-{3-[(2R)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazol-6-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure described inExample 22, substituting 3-methyl-2-pyridone (CAS #1003-56-1) for3(2H)-pyridazinone. ¹H NMR (500 MHz, CDCl₃) δ ppm 8.02 (d, J=8.42 Hz,1H) 7.89 (d, J=2.50 Hz, 1H) 7.42 (dd, J=8.73, 2.18 Hz, 1H) 7.21-7.33 (m,2H) 6.18 (t, J=6.71 Hz, 1H) 3.57-3.67 (m, 1H) 3.15-3.25 (m, 1H)3.01-3.11 (m, 1H) 2.74-2.83 (m, 1H) 2.58-2.65 (m, 1H) 2.43-2.55 (m, 2H)2.29-2.40 (m, 1H) 2.20 (s, 3H) 1.90-2.01 (m, 1H) 1.80-1.89 (m, 1H)1.66-1.75 (m, 1H) 1.46-1.62 (m, 2H) 1.15 (s, 3H). MS: (M+H)⁺=380.

Example 26Trans-2-(2-{3-[(2S)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazol-6-yl)pyridazin-3(2H)-one

The title compound was prepared according to the procedure described inExample 22, substituting the product of Example 11A for the product ofExample 1E. ¹H NMR (500 MHz, CDCl₃) δ ppm 8.15 (d, J=2.18 Hz, 1H) 8.03(d, J=8.73 Hz, 1H) 7.92 (dd, J=3.74, 1.56 Hz, 1H) 7.69 (dd, J=8.73, 2.18Hz, 1H) 7.23-7.30 (m, 1H) 7.08 (dd, J=9.51, 1.72 Hz, 1H) 3.58-3.68 (m,1H) 3.16-3.26 (m, 1H) 3.01-3.11 (m, 1H) 2.75-2.84 (m, 1H) 2.59-2.68 (m,1H) 2.45-2.57 (m, 2H) 2.31-2.41 (m, 1H) 1.92-2.01 (m, 1H) 1.79-1.90 (m,1H) 1.68-1.76 (m, 1H) 1.47-1.62 (m, 2H) 1.16 (s, 3H). MS: (M+H)⁺=367.

Example 27Trans-6-methyl-2-(2-{3-[(2S)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazol-6-yl)pyridazin-3(2H)-one

The title compound was prepared according to the procedure described inExample 22, substituting the product of Example 11A for the product ofExample 1E, and substituting 6-methyl-3(2H)-pyridazinone for3(2H)-pyridazinone. ¹H NMR (500 MHz, CDCl₃) δ ppm 8.12 (m, 1H) 8.00 (m,1H) 7.67 (dd, J=8.73, 1.87 Hz, 1H) 7.16 (m, 1H) 7.01 (m, 1H) 3.57-3.67(m, 1H) 3.15-3.24 (m, 1H) 3.02-3.11 (m, 1H) 2.73-2.86 (m, 1H) 2.56-2.68(m, 1H) 2.45-2.55 (m, 2H) 2.41 (s, 3H) 2.30-2.37 (m, 1H) 1.92-2.04 (m,1H) 1.77-1.87 (m, 1H) 1.67-1.74 (m, 1H) 1.44-1.61 (m, 2H) 1.15 (s, 3H).MS: (M+H)⁺=381.

Example 28Trans-5-methyl-1-(2-{3-[(2S)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazol-6-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure described inExample 22, substituting the product of Example 11A for the product ofExample 1E and substituting 5-methyl-2(1H)-pyridone for3(2H)-pyridazinone. ¹H NMR (500 MHz, CDCl₃) δ ppm 8.02 (d, J=8.42 Hz,1H) 7.88 (d, J=2.18 Hz, 1H) 7.42 (dd, J=8.58, 2.03 Hz, 1H) 7.28 (dd,J=9.36, 2.50 Hz, 1H) 7.15 (s, 1H) 6.62 (d, J=9.36 Hz, 1H) 3.59-3.69 (m,1H) 3.15-3.25 (m, 1H) 3.01-3.10 (m, 1H) 2.77-2.85 (m, 1H) 2.60-2.67 (m,1H) 2.33-2.56 (m, 3H) 2.12 (s, 3H) 1.93-2.03 (m, 1H) 1.79-1.88 (m, 1H)1.68-1.77 (m, 1H) 1.45-1.64 (m, 2H) 1.16 (s, 3H). MS: (M+H)⁺=380.

Example 29Trans-3-methyl-1-(2-{3-[(2S)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazol-6-yl)pyridin-2(1H)-one

The title compound was prepared according to the procedure described inExample 22, substituting the product of Example 11A for the product ofExample 1E and substituting 3-methyl-2-pyridone for 3(2H)-pyridazinone.¹H NMR (500 MHz, CDCl₃) δ ppm 8.02 (d, J=8.74 Hz, 1H) 7.89 (d, J=1.87Hz, 1H) 7.42 (dd, J=8.73, 2.18 Hz, 1H) 7.25-7.31 (m, 2H) 6.18 (t, J=6.86Hz, 1H) 3.57-3.68 (m, 1H) 3.15-3.25 (m, 1H) 3.02-3.10 (m, 1H) 2.72-2.85(m, 1H) 2.59-2.68 (m, 1H) 2.44-2.53 (m, 2H) 2.31-2.43 (m, 1H) 2.20 (s,3H) 1.91-2.02 (m, 1H) 1.79-1.88 (m, 1H) 1.65-1.76 (m, 1H) 1.44-1.64 (m,2H) 1.15 (s, 3H). MS: (M+H)⁺=380.

Example 30Cis-6-pyrimidin-5-yl-2-(3-pyrrolidin-1-ylcyclobutyl)-1,3-benzothiazoleExample 30ACis-6-bromo-2-(3-pyrrolidin-1-ylcyclobutyl)-1,3-benzothiazole

Pyrrolidine (295 μl, 3.54 mmol) was added to a solution of the productof Example 1C (100 mg, 0.354 mmole) in 2 ml methanol and the mixture wasstirred at room temperature for 1 hour. Sodium cyanoborohydride (56 mg,0.891 mmole) was added and the resulting mixture was stirred at roomtemperature overnight. The reaction was quenched with water andextracted three times with dichloromethane. The combined organic layerswere washed with brine, dried over sodium sulfate, filtered, andconcentrated to give the crude product which was purified by columnchromatography (0.5% ammonium hydroxide and 5% methanol indichloromethane) to give 65 mg (55%) of the title compound. ¹H NMR (400MHz, CDCl₃) for the cis isomer δ ppm 7.97 (d, J=1.84 Hz, 1H) 7.80 (d,J=8.90 Hz, 1H) 7.54 (dd, J=8.75, 1.99 Hz, 1H) 3.56-3.66 (m, 1H)3.05-3.19 (m, 1H) 2.55-2.75 (m, 6H) 2.41-2.53 (m, 2H) 1.75-1.92 (m, 4H).MS: (M+H)⁺=337/339.

Example 30BCis-6-pyrimidin-5-yl-2-(3-pyrrolidin-1-ylcyclobutyl)-1,3-benzothiazole

The title compound was prepared according to the procedure described inExample 1F, substituting the product of Example 30A for the product ofExample 1E. ¹H NMR (400 MHz, CDCl₃) δ ppm 9.23 (s, 1H) 9.01 (s, 2H) 8.08(d, J=8.59 Hz, 1H) 8.05 (d, J=1.53 Hz, 1H) 7.65 (dd, J=8.59, 1.84 Hz,1H) 3.59-3.74 (m, 1H) 3.02-3.16 (m, 1H) 2.66-2.79 (m, 2H) 2.51-2.63 (m,4H) 2.38-2.49 (m, 2H) 1.84 (s, 4H). MS: (M+H)⁺=337.

Example 31Cis-6-(2-methoxypyrimidin-5-yl)-2-(3-pyrrolidin-1-ylcyclobutyl)-1,3-benzothiazole

The title compound was prepared according to the procedure described inExample 1F, substituting the product of Example 30A for the product ofExample 1E and substituting 2-methoxypyrimidine-5-boronic acid forpyrimidine-5-boronic acid. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.77 (s, 2H)8.04 (d, J=8.90 Hz, 1H) 7.98 (d, J=1.23 Hz, 1H) 7.58 (dd, J=8.44, 1.99Hz, 1H) 4.08 (s, 3H) 3.60-3.72 (m, 1H) 3.04-3.14 (m, 1H) 2.65-2.78 (m,2H) 2.51-2.63 (m, 4H) 2.38-2.51 (m, 2H) 1.84 (s, 4H). MS: (M+H)⁺=367.

Example 32Cis-2-(3-piperidin-1-ylcyclobutyl)-6-pyrimidin-5-yl-1,3-benzothiazoleExample 32A Cis-6-bromo-2-(3-piperidin-1-ylcyclobutyl)-1,3-benzothiazole

The title compound was prepared according to the procedure described inExample 17A, substituting piperidine for 2-(R)-methylpyrrolidine. ¹H NMR(500 MHz, CDCl₃) δ ppm 7.97 (d, J=1.87 Hz, 1H) 7.79 (d, J=8.73 Hz, 1H)7.53 (dd, J=8.73, 1.87 Hz, 1H) 3.50-3.61 (m, 1H) 2.79 (s, 1H) 2.61-2.71(m, 2H) 2.23-2.43 (m, 6H) 1.52-1.71 (m, 6H). MS: (M+H)⁺=351/353.

Example 32BCis-2-(3-piperidin-1-ylcyclobutyl)-6-pyrimidin-5-yl-1,3-benzothiazole

The title compound was prepared according to the procedure described inExample 1F, substituting the product of Example 32A for the product ofExample 1E. ¹H NMR (500 MHz, CDCl₃) δ ppm 9.23 (s, 1H) 9.01 (s, 2H) 8.08(d, J=9.05 Hz, 1H) 8.05 (d, J=1.25 Hz, 1H) 7.64 (dd, J=8.42, 1.87 Hz,1H) 3.56-3.68 (m, 1H) 2.80-2.88 (m, 1H) 2.66-2.77 (m, 2H) 2.22-2.47 (m,6H) 1.52-1.74 (m, 6H). MS: (M+H)⁺=351.

Example 33Cis-6-(2-methoxypyrimidin-5-yl)-2-(3-piperidin-1-ylcyclobutyl)-1,3-benzothiazole

The title compound was prepared according to the procedure described inExample 1F, substituting the product of Example 32A for the product ofExample 1E, and substituting 2-methoxypyrimidine-5-boronic acid forpyrimidine-5-boronic acid. ¹H NMR (500 MHz, CDCl₃) δ ppm 8.77 (s, 2H)8.04 (d, J=8.42 Hz, 1H) 7.98 (s, 1H) 7.58 (dd, J=8.42, 1.87 Hz, 1H) 4.08(s, 3H) 3.55-3.68 (m, 1H) 2.79-2.91 (m, 1H) 2.66-2.77 (m, 2H) 2.23-2.49(m, 6H) 1.52-1.73 (m, 6H). MS: (M+H)⁺=381.

Example 34Cis-2-(3-azepan-1-ylcyclobutyl)-6-pyrimidin-5-yl-1,3-benzothiazoleExample 34A Cis-2-(3-azepan-1-ylcyclobutyl)-6-bromo-1,3-benzothiazole

The title compound was prepared according to the procedure described inExample 17A, except for substituting hexamethyleneimine for2-(R)-methylpyrrolidine. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.97 (d, J=1.87Hz, 1H) 7.80 (d, J=8.74 Hz, 1H) 7.53 (dd, J=8.58, 2.03 Hz, 1H) 3.45-3.57(m, 1H) 3.02-3.15 (m, 1H) 2.64-2.73 (m, 2H) 2.48-2.62 (m, 4H) 2.20-2.37(m, 2H) 1.51-1.75 (m, 8H). MS: (M+H)⁺=365/367.

Example 34BCis-2-(3-azepan-1-ylcyclobutyl)-6-pyrimidin-5-yl-1,3-benzothiazole

The title compound was prepared according to the procedure described inExample 1F, substituting the product of Example 34A for the compound ofExample 1E. ¹H NMR (400 MHz, CDCl₃) δ ppm 9.23 (s, 1H) 9.01 (s, 2H) 8.09(d, J=8.29 Hz, 1H) 8.05 (d, J=1.23 Hz, 1H) 7.65 (dd, J=8.44, 1.69 Hz,1H) 3.45-3.67 (m, 1H) 3.04-3.21 (m, 1H) 2.67-2.77 (m, 2H) 2.46-2.65 (m,4H) 2.26-2.43 (m, 2H) 1.53-1.78 (m, 8H). MS: (M+H)⁺=365.

Example 35Cis-2-(3-morpholin-4-ylcyclobutyl)-6-pyrimidin-5-yl-1,3-benzothiazoleExample 35A Cis-6-bromo-2-(3-morpholin-4-ylcyclobutyl)-1,3-benzothiazole

The title compound was prepared according to the procedure described inExample 17A, substituting morpholine for 2-(R)-methylpyrrolidine. ¹H NMR(500 MHz, CDCl₃) δ ppm 7.97 (d, J=1.87 Hz, 1H) 7.81 (d, J=8.74 Hz, 1H)7.54 (dd, J=8.58, 2.03 Hz, 1H) 4.01 (d, J=15.29 Hz, 1H) 3.68-3.80 (m,2H) 3.51-3.62 (m, 1H) 3.14 (d, J=13.73 Hz, 1H) 2.81-2.98 (m, 2H)2.64-2.72 (m, 1H) 2.25-2.48 (m, 4H) 1.58 (s, 2H). MS: (M+H)⁺=353/355.

Example 35BCis-2-(3-morpholin-4-ylcyclobutyl)-6-pyrimidin-5-yl-1,3-benzothiazole

The title compound was prepared according to the procedure described inExample 1F, substituting the product of Example 35A for the product ofExample 1E. ¹H NMR (400 MHz, CDCl₃) δ ppm 9.23 (s, 1H) 9.01 (s, 2H) 8.10(d, J=8.29 Hz, 1H) 8.06 (d, J=1.53 Hz, 1H) 7.66 (dd, J=8.29, 1.84 Hz,1H) 3.60-3.87 (m, 3 H) 2.80-3.01 (m, 1H) 2.66-2.78 (m, 2H) 2.30-2.51 (m,4H) 1.58 (s, 4H). MS: (M+H)⁺=353.

Example 36Cis-{(2S)-1-[3-(6-pyrimidin-5-yl-1,3-benzothiazol-2-yl)cyclobutyl]pyrrolidin-2-yl}methanolExample 36ACis-{(2S)-1-[3-(6-bromo-1,3-benzothiazol-2-yl)cyclobutyl]pyrrolidin-2-yl}methanol

The title compound was prepared according to the procedure described inExample 30A, substituting L-prolinol for pyrrolidine. ¹H NMR (400 MHz,CDCl₃) δ ppm 7.97 (d, J=2.15 Hz, 1H) 7.81 (d, J=8.59 Hz, 1H) 7.55 (dd,J=8.59, 1.84 Hz, 1H) 3.50-3.63 (m, 2H) 3.39 (dd, J=10.59, 3.22 Hz, 1H)3.22-3.32 (m, 1H) 3.00-3.13 (m, 1H) 2.70-2.84 (m, 2H) 2.58-2.70 (m, 1H)2.34-2.53 (m, 3H) 1.86-2.01 (m, 1H) 1.68-1.82 (m, 3H). MS:(M+H)⁺=367/369.

Example 36BCis-[(2S)-1-[3-(6-pyrimidin-5-yl-1,3-benzothiazol-2-yl)cyclobutyl]pyrrolidin-2-yl]methanol

The title compound was prepared according to the procedure described inExample 1F, substituting the compound of Example 36A for the product ofExample 1E. ¹H NMR (400 MHz, CDCl₃) δ ppm 9.23 (s, 1H) 9.01 (s, 2H) 8.10(d, J=8.90 Hz, 1H) 8.05 (d, J=1.23 Hz, 1H) 7.66 (dd, J=8.44, 1.99 Hz,1H) 3.53-3.68 (m, 2H) 3.38-3.46 (m, 1H) 3.26-3.35 (m, 1H) 3.02-3.14 (m,1H) 2.74-2.86 (m, 2H) 2.63-2.73 (m, 1H) 2.40-2.57 (m, 3H) 1.86-1.99 (m,1H) 1.71-1.84 (m, 2H) 1.49-1.70 (m, 1H). MS: (M+H)⁺=367.

Example 37Cis-((2S)-1-{3-[6-(2-methoxypyrimidin-5-yl)-1,3-benzothiazol-2-yl]cyclobutyl}pyrrolidin-2-yl)methanol

The title compound was prepared according to the procedure described inExample 1F, substituting the product of Example 36A for the product ofExample 1E and substituting 2-methoxypyrimidine-5-boronic acid forpyrimidine-5-boronic acid. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.77 (s, 2H)8.06 (d, J=8.59 Hz, 1H) 7.98 (d, J=1.53 Hz, 1H) 7.59 (dd, J=8.59, 1.84Hz, 1H) 4.08 (s, 3H) 3.55-3.68 (m, J=7.67 Hz, 2H) 3.36-3.47 (m, 1H)3.25-3.35 (m, 1H) 3.03-3.14 (m, 1H) 2.72-2.87 (m, 2H) 2.61-2.72 (m, 1H)2.40-2.54 (m, 3H) 1.87-2.01 (m, 1H) 1.69-1.85 (m, 2H) 1.51-1.70 (m, 1H).MS: (M+H)⁺=397.

Example 38Cis-2-{3-[(3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]cyclobutyl}-6-pyrimidin-5-yl-1,3-benzothiazoleExample 38ACis-tert-butyl(3aR,6aR)-5-[3-(6-bromo-1,3-benzothiazol-2-yl)cyclobutyl]hexahydropyrrolo[3,4-b]pyrrole-1(2H)-carboxylate

The title compound was prepared according to the procedure described inExample 30A, substituting hexahydro-pyrrolo[3,4-b]pyrrole-1-carboxylicacid tert-butyl ester (prepared according to the procedure thatdescribed in: Q. Li et al., J. Med. Chem.; 39(16), 3070-3088, 1996) forpyrrolidine. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.97 (d, J=1.53 Hz, 1H) 7.81(d, J=8.59 Hz, 1H) 7.54 (dd, J=8.59, 1.84 Hz, 1H) 4.13-4.28 (m, 2H)3.50-3.63 (m, 2H) 3.33-3.46 (m, 2H) 2.93-3.01 (m, 1H) 2.78-2.88 (m, 1H)2.27-2.71 (m, 6H) 1.90-2.02 (m, 1H) 1.66-1.78 (m, 1H) 1.45-1.48 (s, 9H).MS: (M+H)⁺=478/480.

Example 38B Cis-tert-butyl(3aR,6aR)-5-[3-(6-pyrimidin-5-yl-1,3-benzothiazol-2-yl)cyclobutyl]hexahydropyrrolo[3,4-b]pyrrole-1(2H)-carboxylate

The title compound was prepared according to the procedure described inExample 1F, substituting the product of Example 38A for the compound ofExample 1E. ¹H NMR (500 MHz, CDCl₃) δ ppm 9.23 (s, 1H) 9.01 (s, 2H) 8.09(d, J=8.42 Hz, 1H) 8.05 (d, J=1.25 Hz, 1H) 7.65 (dd, J=8.42, 1.87 Hz,1H) 4.15-4.30 (m, 2H) 3.53-3.71 (m, 2H) 3.35-3.49 (m, 2H) 2.95-3.07 (m,1H) 2.81-2.91 (m, 1H) 2.58-2.76 (m, 3H) 2.29-2.52 (m, 3H) 1.91-2.03 (m,1H) 1.68-1.80 (m, 1H) 1.39-1.52 (s, 9H). MS: (M+H)⁺=478.

Example 38CCis-2-{3-[(3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]cyclobutyl}-6-pyrimidin-5-yl-1,3-benzothiazole

The title compound was prepared by mixing the product of Example 38Bwith 1:1 mixture of TFA and dichloromethane. After 2 hours, the solventwas removed under reduced pressure, the residue was basified withsaturated sodium bicarbonate and extracted three times withdichloromethane. The combined organic layers were washed with brine,dried over sodium sulfate, filtered, and concentrated under reducedpressure. The resulting residue was purified by column chromatography(0.5% ammonium hydroxide and 5% methanol in dichloromethane) to providethe title compound. ¹H NMR (500 MHz, CDCl₃) δ ppm 9.19-9.26 (s, 1H) 9.01(s, 2H) 8.09 (d, J=8.54 Hz, 1H) 8.05 (d, J=1.53 Hz, 1H) 7.65 (dd,J=8.54, 1.83 Hz, 1H) 3.81-3.92 (m, 1H) 3.60-3.71 (m, 1H) 3.03-3.12 (m,1H) 2.95-3.03 (m, 1H) 2.87-2.95 (m, 1H) 2.72-2.79 (m, 1H) 2.64-2.71 (m,2H) 2.50-2.62 (m, 3H) 2.32-2.46 (m, 3H) 1.91-2.00 (m, 1H) 1.57-1.67 (m,1H). MS: (M+H)⁺=378.

Example 39Cis-2-{3-[(3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]cyclobutyl}-6-(2-methoxypyrimidin-5-yl)-1,3-benzothiazoleExample 39A Cis-tert-butyl(3aR,6aR)-5-{3-[6-(2-methoxypyrimidin-5-yl)-1,3-benzothiazol-2-yl]cyclobutyl}hexahydropyrrolo[3,4-b]pyrrole-1(2H)-carboxylate

The title compound was prepared according to the procedure described inExample 1F, substituting the product of Example 38A for the product ofExample 1E and substituting 2-methoxypyrimidine-5-boronic acid forpyrimidine-5-boronic acid. ¹H NMR (500 MHz, CDCl₃) δ ppm 8.77 (s, 2H)8.05 (d, J=8.42 Hz, 1H) 7.97 (s, 1H) 7.58 (dd, J=8.42, 1.56 Hz, 1H)4.14-4.29 (m, 2H) 4.08 (s, 3H) 3.54-3.70 (m, 2H) 3.34-3.49 (m, 2H)2.93-3.05 (m, 1H) 2.77-2.91 (m, 1H) 2.52-2.75 (m, 3H) 2.28-2.50 (m, 3H)1.90-2.02 (m, 1H) 1.66-1.81 (m, 1H) 1.46 (s, 9H). MS: (M+H)⁺=508.

Example 39BCis-2-{3-[(3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]cyclobutyl}-6-(2-methoxypyrimidin-5-yl)-1,3-benzothiazole

The title compound was prepared according to the procedure described inExample 38C, substituting the product of Example 39A for the product ofExample 38B. ¹H NMR (500 MHz, CDCl₃) δ ppm 8.77 (s, 2H) 8.05 (d, J=8.54Hz, 1H) 7.97 (s, 1H) 7.58 (dd, J=8.54, 1.83 Hz, 1H) 4.08 (s, 3H)3.85-3.98 (m, 1H) 3.60-3.70 (m, 1H) 3.08-3.16 (m, 1H) 2.90-3.02 (m, 2H)2.73-2.81 (m, 1H) 2.61-2.71 (m, 2H) 2.49-2.60 (m, 3H) 2.31-2.47 (m, 3H)1.93-2.05 (m, 1H) 1.58-1.74 (m, 1H). MS: (M+H)⁺=408.

Example 40Cis-2-{3-[(2R)-2-methylpiperidin-1-yl]cyclobutyl}-6-pyrimidin-5-yl-1,3-benzothiazoleExample 40ACis-6-bromo-2-{3-[(2R)-2-methylpiperidin-1-yl]cyclobutyl}-1,3-benzothiazole

The title compound was prepared according to the procedure described inExample 30A, substituting 2-(R)-methylpiperidine (available fromClariant) for pyrrolidine. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.97 (d, J=2.18Hz, 1H) 7.80 (d, J=8.73 Hz, 1H) 7.53 (dd, J=8.58, 2.03 Hz, 1H) 3.43-3.57(m, 1H) 3.07-3.18 (m, 1H) 2.67-2.81 (m, 2H) 2.51-2.66 (m, 2H) 2.37-2.50(m, 2H) 2.27-2.38 (m, 1H) 2.08 (m, 1H) 1.50-1.68 (m, 4H) 1.29-1.42 (m,1H) 1.06 (d, J=4.99 Hz, 3H). MS: (M+H)⁺=365/367.

Example 40BCis-2-{3-[(2R)-2-methylpiperidin-1-yl]cyclobutyl}-6-pyrimidin-5-yl-1,3-benzothiazole

The title compound was prepared according to the procedure described inExample 1F, substituting the product of Example 40A for the product ofExample 1E. ¹H NMR (400 MHz, CDCl₃) δ ppm 9.17 (s, 1H) 9.15 (s, 2H) 8.39(s, 1H) 8.11 (d, J=8.59 Hz, 1H) 7.89 (dd, J=8.29, 1.53 Hz, 1H) 3.92-4.13(m, 2H) 3.75-3.90 (m, 2H) 3.52-3.63 (m, 1H) 3.03-3.18 (m, 1H) 2.83-3.01(m, 3H) 2.66-2.83 (m, 2H) 1.83-2.06 (m, 2H) 1.56-1.80 (m, 2H) 1.41 (dd,J=18.72, 6.75 Hz, 3H). MS: (M+H)⁺=365.

Example 41Cis-N-isopropyl-N-methyl-N-[3-(6-pyrimidin-5-yl-1,3-benzothiazol-2-yl)cyclobutyl]amineExample 41ACis-N-[3-(6-bromo-1,3-benzothiazol-2-yl)cyclobutyl]-N-isopropyl-N-methylamine

The title compound was prepared according to the procedure described inExample 30A, substituting isopropylmethylamine for pyrrolidine. ¹H NMR(500 MHz, CDCl₃) δ ppm 7.97 (d, J=1.87 Hz, 1H) 7.80 (d, J=8.42 Hz, 1H)7.53 (dd, J=8.58, 2.03 Hz, 1H) 3.47-3.58 (m, 1H) 3.12-3.23 (m, 1H)2.89-3.01 (m, 1H) 2.60-2.71 (m, 2H) 2.23-2.38 (m, 2H) 2.12 (s, 3H) 1.01(d, J=6.55 Hz, 6H). MS: (M+H)⁺=339/341.

Example 41BCis-N-isopropyl-N-methyl-N-[3-(6-pyrimidin-5-yl-1,3-benzothiazol-2-yl)cyclobutyl]amine

The title compound was prepared according to the procedure described inExample 1F, substituting the product of Example 41A for the product ofExample 1E. ¹H NMR (400 MHz, Solvent) δ ppm 9.17 (s, 1H) 9.15 (s, 2H)8.39 (d, J=1.53 Hz, 1H) 8.11 (d, J=8.59 Hz, 1H) 7.89 (dd, J=8.59, 1.84Hz, 1H) 3.96-4.10 (m, 1H) 3.77-3.91 (m, 1H) 3.60-3.78 (m, 1H) 2.86-3.07(m, 3H) 2.69-2.82 (m, 1H) 2.71 (s, 3H) 1.36 (dd, J=30.84, 6.29 Hz, 6H).MS: (M+H)⁺=339.

Example 42Cis-{1-[3-(6-pyrimidin-5-yl-1,3-benzothiazol-2-yl)cyclobutyl]piperidin-4-yl}methanolExample 42ACis-{1-[3-(6-bromo-1,3-benzothiazol-2-yl)cyclobutyl]piperidin-4-yl}methanol

The title compound was prepared according to the procedure described inExample 30A, substituting 4-piperidinemethanol for pyrrolidine. ¹H NMR(500 MHz, CDCl₃) δ ppm 7.97 (d, J=1.83 Hz, 1H) 7.80 (d, J=8.85 Hz, 1H)7.54 (dd, J=8.70, 1.98 Hz, 1H) 3.54-3.60 (m, 1H) 3.51 (d, J=6.41 Hz, 2H)2.94 (d, J=10.37 Hz, 2H) 2.77-2.86 (m, 1H) 2.65-2.72 (m, 2H) 2.26-2.35(m, 2H) 1.73-1.87 (m, 4H) 1.47-1.57 (m, 2H) 1.23-1.34 (m, 2H). MS:(M+H)⁺=381/383.

Example 42BCis-{1-[3-(6-pyrimidin-5-yl-1,3-benzothiazol-2-yl)cyclobutyl]piperidin-4-yl}methanol

The title compound was prepared according to the procedure described inExample 1F, substituting the product of Example 42A for the product ofExample 1E. ¹H NMR (400 MHz, CDCl₃) δ ppm 9.23 (s, 1H) 9.02 (s, 2H)8.03-8.12 (m, 2H) 7.65 (dd, J=8.59, 1.84 Hz, 1H) 3.60-3.71 (m, 1H) 3.53(d, J=6.44 Hz, 2H) 3.04-3.17 (m, 2H) 2.61-3.03 (m, 6H) 2.46-2.59 (m, 2H)1.91-2.04 (m, 1H) 1.73-1.89 (m, 2H) 1.52-1.67 (m, 1H) 1.34-1.49 (m, 1H).MS: (M+H)⁺=381.

Example 43Trans-{1-[3-(6-pyrimidin-5-yl-1,3-benzothiazol-2-yl)cyclobutyl]piperidin-4-yl}methanolExample 43ATrans-{1-[3-(6-bromo-1,3-benzothiazol-2-yl)cyclobutyl]piperidin-4-yl}methanol

The product of Example 1D (0.177 mmole) was dissolved in anhydrousdichloromethane (2 ml). Potassium carbonate (50 mg, 0.362 mmole) wasadded followed by trifluoromethanesulfonic anhydride (40 μl, 0.238mmole). The mixture was allowed to stir at room temperature for 2 hours,then another portion of potassium carbonate (100 mg, 0.724 mmole) wasadded, followed by 4-piperidinemethanol (61 mg, 0.530 mmole). Theresulting mixture was stirred at room temperature overnight. It was thenquenched with water, and extracted three times with dichloromethane. Theorganic layers were combined, washed with brine, dried over sodiumsulfate, and concentrated. The crude product was purified by columnchromatography (0.3% ammonium hydroxide and 3% methanol indichloromethane) to give 29 mg (43%) of title compound. ¹H NMR (500 MHz,CDCl₃) δ ppm 7.98 (d, J=1.83 Hz, 1H) 7.83 (d, J=8.54 Hz, 1H) 7.56 (dd,J=8.54, 1.83 Hz, 1H) 3.74-3.86 (m, 1H) 3.52 (d, J=6.10 Hz, 2H) 3.08-3.19(m, 1H) 2.95 (d, J=10.68 Hz, 2H) 2.51-2.62 (m, 4H) 1.79 (d, J=10.68 Hz,4H) 1.48-1.59 (m, 2H) 1.25-1.38 (m, 2H). MS: (M+H)⁺=381/383.

Example 43BTrans-{1-[3-(6-pyrimidin-5-yl-1,3-benzothiazol-2-yl)cyclobutyl]piperidin-4-yl}methanol

The title compound was prepared according to the procedure described inExample 1F, substituting the product of Example 43A for the product ofExample 1E. ¹H NMR (400 MHz, CDCl₃) δ ppm 9.24 (s, 1H) 9.02 (s, 2H) 8.11(d, J=8.29 Hz, 1H) 8.06 (d, J=1.53 Hz, 1H) 7.67 (dd, J=8.59, 1.84 Hz,1H) 3.86-3.94 (m, 1H) 3.54 (t, J=6.44 Hz, 2H) 3.30-3.51 (m, 3H)3.15-3.24 (m, 2H) 2.84-2.98 (m, 2H) 2.63-2.76 (m, 2H) 1.97-2.12 (m, 2H)1.77-1.90 (m, 2H) 1.44-1.68 (m, 2H). MS: (M+H)⁺=381.

Example 44Trans-2-(3-piperidin-1-ylcyclobutyl)-6-pyrimidin-5-yl-1,3-benzothiazoleExample 44ATrans-6-bromo-2-(3-piperidin-1-ylcyclobutyl)-1,3-benzothiazole

The title compound was prepared according to the procedure described inExample 43A, substituting piperidine for 4-piperidinemethanol. ¹H NMR(400 MHz, CDCl₃) δ ppm 7.97 (d, J=2.15 Hz, 1H) 7.82 (d, J=8.59 Hz, 1H)7.55 (dd, J=8.59, 1.84 Hz, 1H) 3.73-3.87 (m, 1H) 3.05-3.18 (m, 1H)2.49-2.66 (m, 4H) 2.19-2.44 (m, 4H) 1.55-1.71 (m, 4H) 1.39-1.54 (m, 2H).MS: (M+H)⁺=351/353.

Example 44BTrans-2-(3-piperidin-1-ylcyclobutyl)-6-pyrimidin-5-yl-1,3-benzothiazole

The title compound was prepared according to the procedure described inExample 1F, substituting the product of Example 44A for the product ofExample 1E. ¹H NMR (400 MHz, CDCl₃) δ ppm 9.23 (s, 1H) 9.01 (s, 2H) 8.11(d, J=8.29 Hz, 1H) 8.06 (d, J=1.53 Hz, 1H) 7.66 (dd, J=8.29, 1.84 Hz,1H) 3.80-3.94 (m, 1H) 3.09-3.21 (m, 1H) 2.56-2.68 (m, 4H) 2.27-2.42 (m,4H) 1.58-1.70 (m, 4H) 1.42-1.55 (m, 2H). MS: (M+H)⁺=351.

Example 45Trans-6-(2,6-dimethylpyridin-3-yl)-2-(3-piperidin-1-ylcyclobutyl)-1,3-benzothiazole

The title compound was prepared according to the procedure described inExample 1F, substituting the product of Example 44A for the product ofExample 1E and substituting the product of Example 2A forpyrimidine-5-boronic acid. ¹H NMR (500 MHz, CDCl₃) δ ppm 8.02 (d, J=8.24Hz, 1H) 7.76 (s, 1H) 7.47 (d, J=7.63 Hz, 1H) 7.40 (dd, J=8.54, 1.53 Hz,1H) 7.08 (d, J=7.63 Hz, 1H) 3.83-3.92 (m, 1H) 3.42-3.53 (m, 1H)2.92-3.04 (m, 1H) 2.62-2.74 (m, 3H) 2.60 (s, 3H) 2.50 (s, 3H) 2.08 (s,4H) 1.71-1.83 (m, 4H) 1.50-1.61 (m, 2H). MS: (M+H)⁺=378.

Example 46Trans-6-(6-methoxypyridin-3-yl)-2-(3-piperidin-1-ylcyclobutyl)-1,3-benzothiazole

The title compound was prepared according to the procedure described inExample 1F, substituting the product of Example 44A for the product ofExample 1E, and substituting 6-methoxypyridine-3-boronic acid forpyrimidine-5-boronic acid. ¹H NMR (500 MHz, CDCl₃) δ ppm 8.43 (d, J=2.44Hz, 1H) 8.03 (d, J=8.54 Hz, 1H) 7.97 (d, J=1.53 Hz, 1H) 7.84 (dd,J=8.70, 2.59 Hz, 1H) 7.62 (dd, J=8.54, 1.83 Hz, 1H) 6.85 (d, J=8.54 Hz,1H) 4.00 (s, 3H) 3.82-3.93 (m, 1H) 3.36-3.48 (m, 1H) 2.87-2.98 (m, 2H)2.52-2.71 (m, 4H) 2.08 (s, 2H) 1.67-1.82 (m, 4H) 1.48-1.58 (m, 2H). MS:(M+H)⁺=380.

Example 47Trans-6-(2-methoxypyrimidin-5-yl)-2-(3-piperidin-1-ylcyclobutyl)-1,3-benzothiazole

The title compound was prepared according to the procedure described inExample 1F, except for substituting the compound of Example 44A for thecompound of Example 1E, and substituting 2-methoxypyrimidine-5-boronicacid for pyrimidine-5-boronic acid. ¹H NMR (500 MHz, CDCl₃) δ ppm 8.78(s, 2H) 8.07 (d, J=8.54 Hz, 1H) 7.98 (d, J=1.53 Hz, 1H) 7.60 (dd,J=8.39, 1.68 Hz, 1H) 4.09 (s, 3H) 3.80-3.92 (m, 1H) 3.07-3.24 (m, 1H)2.55-2.73 (m, 4H) 2.26-2.47 (m, 4H) 1.57-1.80 (m, 4H) 1.43-1.53 (m, 2H).MS: (M+H)⁺=381.

Example 48ATrans-2-[2-(3-piperidin-1-ylcyclobutyl)-1,3-benzothiazol-6-yl]pyridazin-3(2H)-one

The title compound was prepared according to the procedure described inExample 22, substituting the product of Example 44A for the product ofExample 1E. In this preparation, two isomeric products were obtainedwhich represented the cis- and trans-configurations of the cyclobutanering. The product that had a RF of 0.28 on TLC (TLC conditions 0.5%ammonium hydroxide and 5% methanol in dichloromethane on silica gel) wasseparated and purified by column chromatography on silica gel, elutingwith 0.5% ammonium hydroxide and 5% methanol in dichloromethane to givean off-white solid, which corresponded to the trans isomer: mp 139-140°C. ¹H NMR (500 MHz, CDCl₃) δ ppm 8.15 (d, J=2.14 Hz, 1H) 8.05 (d, J=8.85Hz, 1H) 7.93 (dd, J=3.81, 1.68 Hz, 1H) 7.70 (dd, J=8.85, 2.14 Hz, 1H)7.24-7.31 (m, 1H) 7.09 (dd, J=9.46, 1.83 Hz, 1H) 3.80-3.92 (m, 1H)3.10-3.19 (m, 1H) 2.53-2.70 (m, 4H) 2.21-2.47 (m, 4H) 1.58-1.72 (m, 4H)1.42-1.55 (m, 2H). MS: (M+H)⁺=367.

Alternative Method of Preparing Example 48A

The title compound was prepared according to the procedure described inExample 1E, except for substituting the product of Example 48E for theproduct of Example 1D, and substituting piperidine for2-(R)-methylpyrrolidine L-tartrate. The NMR and mass spectra confirmed amatch with the spectrum of the product prepared in the previous method.

Salt Preparations of Example 48A

A methanolic solution of the title compound when treated withhydrochloric acid (1:1 molar ratio), followed by concentration of thesolution, gave a solid of m.p. 256-259° C. A methanolic solution of thetitle compound when treated with sulfuric acid (1:1 molar ratio),followed by concentration of the solution, gave a solid of m.p. 86-92°C. A methanolic solution of the title compound when treated withortho-phosphoric acid (1:1 molar ratio), followed by concentration ofthe solution, gave a solid of m.p. 110-113° C. A methanolic solution ofthe title compound when treated with L-tartaric acid (1:1 molar ratio),followed by concentration of the solution, gave a solid of m.p. 94-97°C.

Example 48BCis-2-[2-(3-piperidin-1-ylcyclobutyl)-1,3-benzothiazol-6-yl]pyridazin-3(2H)-one

The titled compound was prepared as described in Example 48A to isolatethe other isomer that had a RF of 0.32 on TLC (TLC conditions 0.5%ammonium hydroxide and 5% methanol in dichloromethane on silica gel)corresponded to the cis-isomer as an off-white solid, mp 127-128° C. ¹HNMR (400 MHz, CDCl₃) δ ppm 8.14 (t, J=2.61 Hz, 1H) 8.02 (d, J=8.59 Hz,1H) 7.92 (dd, J=3.68, 1.53 Hz, 1H) 7.66-7.70 (m, 1H) 7.23-7.30 (m, 1H)7.08 (dd, J=9.36, 1.69 Hz, 1H) 3.52-3.65 (m, 1H) 2.75-2.86 (m, 1H)2.62-2.73 (m, 2H) 2.25-2.41 (m, 6H) 1.55-1.66 (m, 4H) 1.41-1.52 (m, 2H).MS: (M+H)⁺=367.

Salt Preparations of Example 48B

A methanolic solution of the title compound when treated withhydrochloric acid (1:1 molar ratio), followed by concentration of thesolution, gave a solid of m.p. 258-261° C. A methanolic solution of thetitle compound when treated with sulfuric acid (1:1 molar ratio),followed by concentration of the solution, gave a solid of m.p. 105-110°C. A methanolic solution of the title compound when treated withortho-phosphoric acid (1:1 molar ratio), followed by concentration ofthe solution, gave a solid of m.p. 206-209° C. A methanolic solution ofthe title compound when treated with L-tartaric acid (1:1 molar ratio),followed by concentration of the solution, gave a solid of m.p. 136-140°C.

Alternative Preparation of Example 48B Example 48C2-[2-(3-hydroxy-cyclobutyl)-1,3-benzothiazol-6-yl]-2H-pyridazin-3-one

The product of Example 1D(cis-3-(6-Bromo-benzothiazol-2-yl)-cyclobutanol) (2.25 g, 7.93 mmole),3(2H)-pyridazinone (CAS # 504-30-3) (1.52 g, 15.83 mmole), copper (500mg, 7.93 mmole), potassium carbonate (3.28 g, 23.77 mmole), andcopper(I) iodide (211 mg, 1.11 mmole) were mixed in degassed pyridine(50 ml) and placed under vacuum for 15 minutes then refilled withnitrogen. N,N′-dimethylethylene diamine (240 μl, 196 mg, 2.22 mmole) wasadded and the mixture was heated at reflux overnight. The mixture wasdiluted with water and extracted three times with dichloromethane. Thecombined organic layers were washed with brine, dried over sodiumsulfate, filtered, and concentrated under reduced pressure to give thecrude product which was purified by column chromatography (0.4% ammoniumhydroxide and 4% methanol in dichloromethane) to provide the titlecompound. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.15 (d, J=2.15 Hz, 1H) 8.04 (d,J=8.90 Hz, 1H) 7.92 (dd, J=3.68, 1.53 Hz, 1H) 7.70 (dd, J=8.59, 2.15 Hz,1H) 7.24-7.30 (m, 1H) 7.04-7.11 (m, 1H) 4.68-4.81 (m, 0.3H) 4.31-4.43(m, 0.7H) 3.87-3.98 (m, 0.3H) 3.39-3.51 (m, 0.7H) 2.90-3.01 (m, 1.4H)2.77-2.87 (m, 0.6H) 2.51-2.62 (m, 0.6H) 2.33-2.45 (m, 2.1H) 2.07 (d,J=5.22 Hz, 0.3H). MS: (M+H)⁺=300.

Example 48D2-[2-(3-oxo-cyclobutyl)-1,3-benzothiazol-6-yl]-2H-pyridazin-3-one

The product of Example 48C (1.63 g, 5.45 mmole) was dissolved in 50 mlanhydrous dichloromethane. Dess-Martin periodinane (3.0 g, 7.07 mmole,[87413-09-0]) was added. After 3 hours at room temperature, the mixturewas diluted with water and extracted three times with dichloromethane.The combined organic layers were washed with brine, dried over sodiumsulfate, filtered, and concentrated under reduced pressure to providethe crude product which was purified by column chromatography (0.25%ammonium hydroxide and 2.5% methanol in dichloromethane) to provide thetitle compound. ¹H NMR (300 MHz, CDCl₃) δ ppm 8.20 (d, J=2.03 Hz, 1H)8.07 (d, J=8.82 Hz, 1H) 7.94 (dd, J=3.73, 1.70 Hz, 1H) 7.75 (dd, J=8.82,2.37 Hz, 1H) 7.26-7.31 (m, 1H) 7.09 (dd, J=9.49, 1.70 Hz, 1H) 4.01-4.15(m, 1H) 3.54-3.79 (m, 5H). MS: (M+H)⁺=298.

Example 48ECis-2-[2-(3-hydroxy-cyclobutyl)-1,3-benzothiazol-6-yl]-2H-pyridazin-3-one

The product of 48D (213 mg, 0.72 mmole) was dissolved in 6 ml ofmethanol and 3 ml of dichloromethane and cooled in an ice bath. Sodiumborohydride (60 mg, 1.62 mmole) was added and the mixture was stirred atthis temperature for 30 minutes. The mixture was diluted with water,stirred for 1 hour and extracted three times with dichloromethane. Thecombined organic layers were washed with brine, dried over sodiumsulfate, filtered, and concentrated under reduced pressure to providethe title compound. ¹H NMR (300 MHz, CDCl₃) δ ppm 8.16 (d, J=2.37 Hz,1H) 8.05 (d, J=8.82 Hz, 1H) 7.93 (dd, J=3.73, 1.70 Hz, 1H) 7.70 (dd,J=8.82, 2.03 Hz, 1H) 7.25-7.30 (m, 1H) 7.08 (dd, J=9.49, 1.70 Hz, 1H)4.38 (m, 1H) 3.37-3.54 (m, 1H) 2.90-3.05 (m, 2H) 2.31-2.46 (m, 2H)2.19-2.28 (m, 1H). MS: (M+H)⁺=300.

Example 48BCis-2-[2-(3-piperidin-1-ylcyclobutyl)-1,3-benzothiazol-6-yl]pyridazin-3(2H)-one

The title compound was prepared according to the procedure described inExample 30A, except for substituting the product of Example 48D for theproduct of Example 1C, and substituting piperidine for pyrrolidine. TheNMR and mass spectra confirmed a match with the spectrum of the productprepared in the previous method.

Example 49Trans-6-methyl-2-[2-(3-piperidin-1-ylcyclobutyl)-1,3-benzothiazol-6-yl]pyridazin-3(2H)-one

The title compound was prepared according to the procedure described inExample 22, substituting the product of Example 44A for the product ofExample 1E and substituting 6-methyl-3(2H)-pyridazinone for3(2H)-pyridazinone. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.12 (d, J=2.15 Hz,1H) 8.01 (d, J=8.90 Hz, 1H) 7.67 (dd, J=8.90, 2.15 Hz, 1H) 7.16 (d,J=9.51 Hz, 1H) 7.00 (d, J=9.51 Hz, 1H) 3.52-3.64 (m, 1H) 2.72-2.86 (m,1H) 2.53-2.73 (m, 2H) 2.40 (s, 3H) 2.24-2.38 (m, 4H) 1.65-1.75 (m, 2H)1.54-1.65 (m, 4H) 1.46 (d, J=4.91 Hz, 2H). MS: (M+H)⁺=381.

Example 50Trans-3-methyl-1-[2-(3-piperidin-1-ylcyclobutyl)-1,3-benzothiazol-6-yl]pyridin-2(1H)-one

The title compound was prepared according to the procedure described inExample 22, substituting the product of Example 44A for the product ofExample 1E and substituting 3-methyl-2-pyridone for 3(2H)-pyridazinone.¹H NMR (400 MHz, CDCl₃) δ ppm 8.02 (d, J=8.59 Hz, 1H) 7.89 (d, J=2.15Hz, 1H) 7.42 (dd, J=8.75, 1.99 Hz, 1H) 7.22-7.34 (m, 2H) 6.19 (t, J=6.75Hz, 1H) 3.53-3.68 (m, 1H) 2.80-2.94 (m, 1H) 2.51-2.91 (m, 3H) 2.32-2.50(m, 4H) 2.20 (s, 3H) 1.99-2.12 (m, 1H) 1.58-1.73 (m, 4H) 1.43-1.54 (m,2H). MS: (M+H)⁺=380.

Example 51Trans-6-(1-methyl-1H-pyrazol-4-yl)-2-(3-piperidin-1-ylcyclobutyl)-1,3-benzothiazoleExample 51ATrans-2-(3-piperidin-1-ylcyclobutyl)-6-(1-trityl-1H-pyrazol-4-yl)-1,3-benzothiazole)

The product of Example 44A (120 mg, 0.34 mmole),4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-trityl-1H-pyrazole(224 mg, 0.51 mmole), dichlorobis-(triphenylphosphine)palladium(II)(14.0 mg, 0.020 mmole), 2-(dicyclohexyl-phosphino)biphenyl (7.0 mg,0.020 mmole), sodium carbonate (1 M solution, 0.51 ml, 0.51 mmole) and1.5 ml of ethanol/dioxane (1:1) were combined under N₂ in a capped,sealed vial. The vial was sealed and was placed a commercial (i.e. EmrysCreator) microwave for 10 minutes at 140° C. The reaction mixture wasquenched with water and extracted with dichloromethane (4×5 ml). Thecombined organic layers were washed with brine, dried over sodiumsulfate, filtered, and concentrated to give the crude product which waspurified by column chromatography (1% ammonium hydroxide and 10%methanol in dichloromethane) to give 138.1 mg (70% yield) of titlecompound. ¹H NMR (300 MHz, CDCl₃) δ ppm 7.99 (s, 1H), 7.89 (d, J=8.31Hz, 1H), 7.88 (d, J=2.03 Hz, 1H), 7.68 (s, 1H), 7.53 (dd, J=8.31, 1.87Hz, 1H), 7.52-7.35 (m, 9H), 7.19-7.23 (m, 6H), 3.93 (m, 1H) 3.42 (m, 1H)2.61-2.73 (m, 2H) 2.26-2.52 (m, 4H) 1.73-1.90 (m, 4H) 1.43-1.58 (m, 4H).MS: (M+H)⁺=581.

Example 51BTrans-2-(3-piperidin-1-ylcyclobutyl)-6-(1H-pyrazol-4-yl)-1,3-benzothiazole

The product of Example 51A (135.0 mg, 0.23 mmole) was dissolved informic acid (88%, 2 ml) and stirred at room temperature for 2 hours. Thereaction mixture concentrated was under reduced pressure. The solidresidue was then treated with saturated aqueous sodium bicarbonate andextracted with dichloromethane (4×5 ml). The combined organic layerswere washed with brine, dried over sodium sulfate, filtered, andconcentrated to give the crude product which was purified by columnchromatography (1% ammonium hydroxide and 10% methanol indichloromethane) to give 71.2 mg (90.5%) of title compound. MS:(M+H)⁺=339.

Example 51CTrans-6-(1-methyl-1H-pyrazol-4-yl)-2-(3-piperidin-1-ylcyclobutyl)-1,3-benzothiazole

The product of Example 51B (34.0 mg, 0.10 mmole) was dissolved in DMF (2ml) and then cooled to 0° C. NaH (60%, 44.0 mg, 1.1 mmol) was addedunder N₂, and the reaction was stirred at 0° C. for 0.5 hours.Iodomethane (6.8 μl, 0.11 mmole) was added, and the reaction mixture wasstirred at 0° C. for 1 hour, and then slowly raised to room temperature.The mixture was quenched with saturated aqueous sodium bicarbonate andextracted with dichloromethane (4×5 ml). The combined organic layerswere washed with brine, dried over sodium sulfate, filtered, andconcentrated to give the crude product which was purified by columnchromatography (10% methanol in dichloromethane) to give 23.8 mg (67.6%)of title compound. ¹H NMR (300 MHz, CDCl₃) δ ppm 7.94 (d, J=8.48 1H)7.93 (d, J=2.03 1H) 7.80 (s, 1H) 7.66, (s, 1H) 7.56 (dd, J=8.48, 2.031H) 3.80 (s, 3H) 3.87 (m, 1H) 3.27 (m, 1H) 2.38-2.62 (m, 4H) 1.49-1.76(m, 6H). MS: (M+H)⁺=353.

Example 52Trans-N-isopropyl-N-methyl-N-[3-(6-pyrimidin-5-yl-1,3-benzothiazol-2-yl)cyclobutyl]amineExample 52ATrans-N-[3-(6-bromo-1,3-benzothiazol-2-yl)cyclobutyl]-N-isopropyl-N-methylamine

The title compound was prepared according to the procedure described inExample 43A, substituting isopropyl-methylamine for4-piperidinemethanol. ¹H NMR (300 MHz, CDCl₃) δ ppm 7.99 (d, J=1.36 Hz,1H) 7.83 (d, J=9.15 Hz, 1H) 7.57 (dd, J=8.81, 2.03 Hz, 1H) 3.80-3.96 (m,2H) 3.28-3.42 (m, 1H) 2.90-3.10 (m, 2H) 2.58-2.77 (m, 2H) 2.40 (s, 3H)1.23 (d, J=5.76 Hz, 6H). MS: (M+H)⁺=339/341.

Example 52BTrans-N-isopropyl-N-methyl-N-[3-(6-pyrimidin-5-yl-1,3-benzothiazol-2-yl)cyclobutyl]amine

The title compound was prepared according to the procedure described inExample 1F, substituting the product of Example 52A for the product ofExample 1E. ¹H NMR (300 MHz, CDCl₃) δ ppm 9.24 (s, 1H) 9.02 (s, 2H) 8.12(d, J=8.48 Hz, 1H) 8.07 (d, J=1.70 Hz, 1H) 7.67 (dd, J=8.48, 1.70 Hz,1H) 3.78-3.93 (m, 1H) 3.61 (m, 1H) 3.06 (m, 1H) 2.67-2.81 (m, 1H) 2.61(t, J=9.16 Hz, 2H) 2.11-2.26 (m, 2H) 1.48-1.75 (m, 4H) 0.94-1.17 (m,4H). MS: (M+H)⁺=339.

Example 53Trans-N-isopropyl-N-{3-[6-(2-methoxypyrimidin-5-yl)-1,3-benzothiazol-2-yl]cyclobutyl}-N-methylamine

The title compound was prepared according to the procedure described inExample 1F, substituting the product of Example 52A for the product ofExample 1E and substituting 2-methoxypyrimidine-5-boronic acid forpyrimidine-5-boronic acid. ¹H NMR (500 MHz, CDCl₃) δ ppm 8.77 (s, 2H)8.07 (d, J=8.42 Hz, 1H) 7.98 (d, J=1.87 Hz, 1H) 7.60 (dd, J=8.42, 1.87Hz, 2H) 4.09 (s, 3H) 3.76-3.89 (m, 1H) 3.51-3.66 (m, 1H) 2.95-3.05 (m,1H) 2.53-2.74 (m, 4H) 2.14 (s, 3H) 1.03 (d, J=6.55 Hz, 6H). MS:(M+H)⁺=369.

Example 54Trans-N-isopropyl-N-{3-[6-(6-methoxypyridin-3-yl)-1,3-benzothiazol-2-yl]cyclobutyl}-N-methylamine

The title compound was prepared according to the procedure described inExample 1F, substituting the product of Example 52A for the product ofExample 1E and substituting 6-methoxypyridine-3-boronic acid forpyrimidine-5-boronic acid. ¹H NMR (300 MHz, CDCl₃) δ ppm 8.00 (d, J=8.48Hz, 1H) 7.87 (d, J=1.70 Hz, 1H) 7.68 (dd, J=9.16, 2.71 Hz, 1H) 7.49 (dd,J=8.48, 1.70 Hz, 1H) 7.39-7.44 (m, 1H) 6.70 (d, J=9.49 Hz, 1H) 3.75-3.88(m, 1H) 3.65 (s, 3H) 3.56-3.63 (m, 1H) 3.00-3.16 (m, 1H) 2.66-2.80 (m,2H) 2.52-2.65 (m, 2H) 2.18 (s, 3H) 1.05 (d, J=6.44 Hz, 6H). MS:(M+H)⁺=368.

Example 55Trans-N-isopropyl-N-{3-[6-(2-methoxypyridin-3-yl)-1,3-benzothiazol-2-yl]cyclobutyl}-N-methylamine

The title compound was prepared according to the procedure described inExample 1F, substituting the product of Example 52A for the product ofExample 1E and substituting 2-methoxypyridine-3-boronic acid forpyrimidine-5-boronic acid. ¹H NMR (500 MHz, CDCl₃) δ ppm 8.19 (dd,J=4.99, 1.87 Hz, 1H) 7.97-8.05 (m, 2H) 7.66 (dd, J=7.18, 1.87 Hz, 1H)7.63 (dd, J=8.42, 1.87 Hz, 1H) 7.00 (dd, J=7.49, 4.99 Hz, 1H) 3.99 (s,3H) 3.78-3.85 (m, 1H) 3.53-3.63 (m, 1H) 2.92-3.09 (m, 1H) 2.63-2.73 (m,2H) 2.52-2.61 (m, 3H) 2.14 (d, J=5.93 Hz, 3H) 0.96-1.08 (m, 6H). MS:(M+H)⁺=368.

Example 56Trans-N-{3-[6-(2,6-dimethylpyridin-3-yl)-1,3-benzothiazol-2-yl]cyclobutyl}-N-isopropyl-N-methylamine

The title compound was prepared according to the procedure described inExample 1F, except for substituting the product of Example 52A for theproduct of Example 1E and substituting the product of Example 2A forpyrimidine-5-boronic acid. MS: (M+H)⁺=366.

Example 57Trans-2-(2-{3-[isopropyl(methyl)amino]cyclobutyl}-1,3-benzothiazol-6-yl)pyridazin-3(2H)-one

The title compound was prepared according to the procedure described inExample 22, except for substituting the product of Example 52A for theproduct of Example 1E. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.14 (d, J=1.84 Hz,1H) 8.03 (d, J=8.59 Hz, 1H) 7.92 (dd, J=3.68, 1.53 Hz, 1H) 7.68 (dd,J=8.90, 2.15 Hz, 1H) 7.24-7.29 (m, 1H) 7.08 (dd, J=9.51, 1.53 Hz, 1H)3.53-3.65 (m, 1H) 3.13-3.28 (m, 1H) 2.90-3.06 (m, 1H) 2.61-2.74 (m, 2H)2.28-2.45 (m, 2H) 2.15 (s, 3H) 1.04 (d, J=6.14 Hz, 6H). MS: (M+H)⁺=355.

Example 58Trans-2-(2-{3-[isopropyl(methyl)amino]cyclobutyl}-1,3-benzothiazol-6-yl)-6-methylpyridazin-3(2H)-one

The title compound was prepared according to the procedure described inExample 22, except for substituting the product of Example 52A for theproduct of Example 1E and substituting 6-methyl-3(2H)-pyridazinone for3(2H)-pyridazinone. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.12 (d, J=1.84 Hz,1H) 8.01 (d, J=8.90 Hz, 1H) 7.67 (dd, J=8.59, 2.15 Hz, 1H) 7.16 (d,J=9.51 Hz, 1H) 7.00 (d, J=9.51 Hz, 1H) 3.49-3.66 (m, 1H) 3.12-3.28 (m,1H) 2.91-3.06 (m, 1H) 2.61-2.75 (m, 2H) 2.40 (s, 3H) 2.29-2.40 (m, 2H)2.14 (s, 3H) 1.03 (d, J=6.75 Hz, 6H). MS: (M+H)⁺=369.

Example 59Trans-1-(2-{3-[isopropyl(methyl)amino]cyclobutyl}-1,3-benzothiazol-6-yl)-3-methylpyridin-2(1H)-one

The title compound was prepared according to the procedure described inExample 22, except for substituting the product of Example 52A for theproduct of Example 1E and substituting 3-methyl-2-pyridone for3(2H)-pyridazinone. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.02 (d, J=8.59 Hz,1H) 7.89 (d, J=1.84 Hz, 1H) 7.42 (dd, J=8.75, 1.99 Hz, 1H) 7.23-7.34 (m,2H) 6.18 (t, J=6.75 Hz, 1H) 3.52-3.63 (m, 1H) 3.12-3.27 (m, 1H)2.90-3.03 (m, 1H) 2.55-2.73 (m, 2H) 2.25-2.44 (m, 2H) 2.20 (s, 3H) 2.13(s, 3H) 1.02 (d, J=6.44 Hz, 6H). MS: (M+H)⁺=368.

Example 60Trans-1-(2-{3-[isopropyl(methyl)amino]cyclobutyl}-1,3-benzothiazol-6-yl)-5-methylpyridin-2(1H)-one

The title compound was prepared according to the procedure described inExample 22, except for substituting the product of Example 52A for theproduct of Example 1E and substituting 5-methyl-2-pyridone for3(2H)-pyridazinone. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.02 (d, J=8.59 Hz,1H) 7.88 (d, J=2.15 Hz, 1H) 7.42 (dd, J=8.59, 1.84 Hz, 1H) 7.26-7.30 (m,1H) 7.15 (s, 1H) 6.62 (d, J=9.21 Hz, 1H) 3.51-3.64 (m, 1H) 3.13-3.27 (m,1H) 2.90-3.02 (m, 1H) 2.62-2.72 (m, 2H) 2.28-2.40 (m, 2H) 2.13 (s, 3H)2.12 (s, 3H) 1.02 (d, J=6.44 Hz, 6H). MS: (M+H)⁺=368.

Example 61Trans-2-(3-azetidin-1-ylcyclobutyl)-6-pyrimidin-5-yl-1,3-benzothiazoleExample 61ATrans-2-(3-azetidin-1-ylcyclobutyl)-6-bromo-1,3-benzothiazole

The title compound was prepared according to the procedure described inExample 43A, except for substituting azetidine for 4-piperidinemethanol.¹H NMR (300 MHz, CDCl₃) δ ppm 7.97 (d, J=2.03 Hz, 1H) 7.82 (d, J=8.48Hz, 1H) 7.56 (dd, J=8.48, 2.03 Hz, 1H) 3.95-4.09 (m, 1H) 3.80-3.91 (m,1H) 3.55-3.75 (m, 2H) 3.19-3.36 (m, 2H) 2.78-2.94 (m, 2H) 2.44-2.62 (m,2H) 2.05-2.23 (m, 2H). MS: (M+H)⁺=323/325.

Example 61BTrans-2-(3-azetidin-1-ylcyclobutyl)-6-pyrimidin-5-yl-1,3-benzothiazole

The title compound was prepared according to the procedure described inExample 1F, except for substituting the product of Example 61A for theproduct of Example 1E. ¹H NMR (400 MHz, CDCl₃) δ ppm 9.23 (s, 1H) 9.01(s, 2H) 8.11 (d, J=8.29 Hz, 1H) 8.05 (d, J=1.53 Hz, 1H) 7.66 (dd,J=8.44, 1.69 Hz, 1H) 3.98-4.12 (m, 1H) 3.60-3.74 (m, 1H) 3.26-3.45 (m,4H) 2.53-2.69 (m, 2H) 2.42-2.54 (m, 2H) 2.16 (m, 2H). MS: (M+H)⁺=323.

Example 62Trans-6-pyrimidin-5-yl-2-(3-pyrrolidin-1-ylcyclobutyl)-1,3-benzothiazoleExample 62ATrans-6-bromo-2-(3-pyrrolidin-1-ylcyclobutyl)-1,3-benzothiazole

The title compound was prepared according to the procedure described inExample 43A, except for substituting pyrrolidine for4-piperidinemethanol. ¹H NMR (300 MHz, CDCl₃) δ ppm 7.98 (d, J=2.03 Hz,1H) 7.82 (d, J=8.82 Hz, 1H) 7.56 (dd, J=8.65, 1.87 Hz, 1H) 3.90-4.04 (m,1H) 3.47 (d, J=7.12 Hz, 1H) 2.55-2.90 (m, 8H) 1.93 (m, 4H). MS:(M+H)⁺=337/339.

Example 62BTrans-6-pyrimidin-5-yl-2-(3-pyrrolidin-1-ylcyclobutyl)-1,3-benzothiazole

The title compound was prepared according to the procedure described inExample 1F, substituting the product of Example 62A for the product ofExample 1E. ¹H NMR (400 MHz, CDCl₃) δ ppm 9.23 (s, 1H) 9.01 (s, 2H) 8.11(d, J=8.59 Hz, 1H) 8.06 (d, J=1.84 Hz, 1H) 7.66 (dd, J=8.59, 1.84 Hz,1H) 3.91-4.09 (m, 1H) 3.20-3.40 (m, 1H) 2.60-2.74 (m, 4H) 2.50-2.58 (m,4H) 1.78-1.92 (m, 4H). MS: (M+H)⁺=337.

Example 63Trans-6-(2,6-dimethylpyridin-3-yl)-2-(3-pyrrolidin-1-ylcyclobutyl)-1,3-benzothiazole

The title compound was prepared according to the procedure described inExample 1F. substituting the product of Example 62A for the product ofExample 1E and substituting the product of Example 2A forpyrimidine-5-boronic acid. ¹H NMR (300 MHz, CDCl₃) δ ppm 8.02 (d, J=8.48Hz, 1H) 7.76 (d, J=1.36 Hz, 1H) 7.45 (d, J=7.80 Hz, 1H) 7.40 (dd,J=8.31, 1.86 Hz, 1H) 7.07 (d, J=7.80 Hz, 1H) 3.95-4.07 (m, 1H) 3.25-3.45(m, 1H) 2.59 (s, 3H) 2.50 (s, 3H) 2.43-2.78 (m, 6H) 1.77-2.00 (m, 4H)1.47-1.68 (m, 2H). MS: (M+H)⁺=364.

Example 64Trans-6-(2-methoxypyrimidin-5-yl)-2-(3-pyrrolidin-1-ylcyclobutyl)-1,3-benzothiazole

The title compound was prepared according to the procedure described inExample 1F, substituting the product of Example 62A for the product ofExample 1E and substituting 2-methoxypyrimidine-5-boronic acid forpyrimidine-5-boronic acid. ¹H NMR (300 MHz, CDCl₃) δ ppm 8.78 (s, 1H)8.07 (d, J=8.48 Hz, 1H) 7.98 (d, J=1.70 Hz, 1H) 7.60 (dd, J=8.48, 2.03Hz, 1H) 4.08 (s, 3H) 3.93-4.07 (m, 1H) 3.26-3.45 (m, 1H) 2.50-2.80 (m,6H) 1.78-1.96 (m, 4H) 1.59 (m, 2H). MS: (M+H)⁺=367.

Example 65Trans-6-(2,4-dimethoxypyrimidin-5-yl)-2-(3-pyrrolidin-1-ylcyclobutyl)-1,3-benzothiazole

The title compound was prepared according to the procedure described inExample 1F, substituting the product of Example 62A for the product ofExample 1E and substituting 2,6-dimethoxy-5-pyrimidineboronic acid forpyrimidine-5-boronic acid. ¹H NMR (300 MHz, CDCl₃) δ ppm 8.32 (s, 1H)8.02 (d, J=8.48 Hz, 1H) 7.97 (d, J=1.70 Hz, 1H) 7.57 (dd, J=8.65, 1.86Hz, 1H) 4.03-4.10 (s, 3H) 3.95-4.03 (m, 1H) 3.26-3.42 (m, 1H) 2.43-2.78(m, 6H) 1.79-1.98 (m, 4H) 1.45-1.66 (m, 2H). MS: (M+H)⁺=397.

Example 66Trans-6-(6-methoxypyridin-3-yl)-2-(3-pyrrolidin-1-ylcyclobutyl)-1,3-benzothiazole

The title compound was prepared according to the procedure described inExample 1F, substituting the product of Example 62A for the product ofExample 1E and substituting 6-methoxy-3-pyridineboronic acid forpyrimidine-5-boronic acid. ¹H NMR (300 MHz, CDCl₃) δ ppm 8.43 (d, J=2.37Hz, 1H) 8.03 (d, J=8.48 Hz, 1H) 7.97 (s, 1H), 7.83 (dd, J=8.65, 2.54 Hz,1H) 7.61 (dd, J=8.48, 2.03 Hz, 1H) 6.85 (d, J=9.15 Hz, 1H) 4.01-4.10 (m,J=6.78 Hz, 1H) 4.00 (s, 3H) 3.35-3.70 (m, 1H) 2.68 (s, 6H) 1.93 (s, 2H)1.93 (s, 4H) 1.46-1.65 (m, 2H). MS: (M+H)⁺=366.

Example 67Trans-2-[2-(3-pyrrolidin-1-ylcyclobutyl)-1,3-benzothiazol-6-yl]pyridazin-3(2H)-one

The title compound was prepared according to the procedure described inExample 22, substituting the product of Example 62A for the product ofExample 1E. ¹H NMR (300 MHz, CDCl₃) δ ppm 8.15 (t, J=1.86 Hz, 1H) 8.04(dd, J=8.65, 7.63 Hz, 1H) 7.89-7.95 (dt, 1H) 7.72 (td, 1H) 7.21-7.31 (m,1H) 7.04-7.15 (dt, 1H) 4.03 (m, 1H) 3.65 (m, 1H) 2.46-2.77 (m, 6H)1.75-2.00 (m, 4H) 1.49-1.62 (m, 2H). MS: (M+H)⁺=353.

Example 68Trans-6-methyl-2-[2-(3-pyrrolidin-1-ylcyclobutyl)-1,3-benzothiazol-6-yl]pyridazin-3(2H)-one

The title compound was prepared according to the procedure described inExample 22, substituting the product of Example 62A for the product ofExample 1E and substituting 6-methyl-3(2H)-pyridazinone for3(2H)-pyridazinone. ¹H NMR (300 MHz, CDCl₃) δ ppm 8.12 (t, J=2.03 Hz,1H) 8.03 (t, J=8.48 Hz, 1H) 7.66 (dd, J=8.48, 2.37 Hz, 1H) 7.17 (d,J=9.49, 1H) 7.00 (d, J=9.49 Hz, 1H) 3.56-3.72 (m, 1H) 3.07 (m, 1H)2.48-2.78 (m, 6H) 2.41 (s, 3H) 1.87-1.96 (m, 2H) 1.77-1.87 (m, 2H)1.49-1.73 (m, 2H). MS: (M+H)⁺=367.

Example 69Trans-5-methyl-1-[2-(3-pyrrolidin-1-ylcyclobutyl)-1,3-benzothiazol-6-yl]pyridin-2(1H)-one

The title compound was prepared according to the procedure described inExample 22, substituting the product of Example 62A for the product ofExample 1E and substituting 5-methyl-2(1H)-pyridone for3(2H)-pyridazinone. ¹H NMR (300 MHz, CDCl₃) δ ppm 8.03 (d, J=9.15 Hz,1H) 7.87-7.90 (m, 1H) 7.44 (td, J=9.00, 2.03 Hz, 1H) 7.29 (dt, J=9.00,2.37 Hz, 2H) 7.15 (s, 1H) 6.63 (d, J=9.15 Hz, 1H) 3.61-3.73 (m, 1H)3.03-3.16 (m, 1H) 2.43-2.78 (m, 6H) 2.12 (s, 3H) 1.81-1.91 (m, 4H)1.51-1.61 (m, 2H). MS: (M+H)⁺=366.

Example 70Trans-3-methyl-1-[2-(3-pyrrolidin-1-ylcyclobutyl)-1,3-benzothiazol-6-yl]pyridin-2(1H)-one

The title compound was prepared according to the procedure described inExample 22, substituting the product of Example 62A for the product ofExample 1E and substituting 3-methyl-2-pyridone for 3(2H)-pyridazinone.¹H NMR (300 MHz, CDCl₃) δ ppm 8.03 (t, J=8.31 Hz, 1H) 7.89 (d, J=2.03Hz, 1H) 7.44 (t, 1H) 7.27-7.33 (m, 1H) 6.18 (q, 2H) 3.55-3.75 (m, 1H)3.03-3.15 (m, 1H) 2.39-2.76 (m, 6H) 2.21 (s, 3H) 1.79-1.99 (m, 4H)1.50-1.70 (m, 2H). MS: (M+H)⁺=366.

Example 71Trans-2-(3-azepan-1-ylcyclobutyl)-6-pyrimidin-5-yl-1,3-benzothiazoleExample 71A Trans-2-(3-azepan-1-ylcyclobutyl)-6-bromo-1,3-benzothiazole

The title compound was prepared according to the procedure described inExample 43A, substituting hexamethyleneimine for 4-piperidinemethanol.¹H NMR (500 MHz, CDCl₃) δ ppm 7.98 (d, J=1.83 Hz, 1H) 7.82 (d, J=8.54Hz, 1H) 7.56 (dd, J=8.54, 1.83 Hz, 1H) 3.73-3.85 (m, 1H) 3.29-3.42 (m,1H) 2.46-2.62 (m, 8H) 1.52-1.74 (m, 8H). MS: (M+H)⁺=365/367.

Example 71BTrans-2-(3-azepan-1-ylcyclobutyl)-6-pyrimidin-5-yl-1,3-benzothiazole

The title compound was prepared according to the procedure described inExample 1F, except for substituting the product of Example 71A for theproduct of Example 1E. ¹H NMR (400 MHz, CDCl₃) δ ppm 9.23 (s, 1H) 9.01(s, 2H) 8.11 (d, J=7.98 Hz, 1H) 8.06 (d, J=1.84 Hz, 1H) 7.66 (dd,J=8.29, 1.84 Hz, 1H) 3.73-3.95 (m, J=6.29, 6.29 Hz, 1H) 3.34-3.50 (m,1H) 2.48-2.69 (m, 8H) 1.59-1.82 (m, 8H). MS: (M+H)⁺=365.

Example 72Trans-2-(3-morpholin-4-ylcyclobutyl)-6-pyrimidin-5-yl-1,3-benzothiazoleExample 72ATrans-6-bromo-2-(3-morpholin-4-ylcyclobutyl)-1,3-benzothiazole

The title compound was prepared according to the procedure described inExample 43A, substituting morpholine for 4-piperidinemethanol. ¹H NMR(300 MHz, CDCl₃) δ ppm 7.98 (d, J=2.03 Hz, 1H) 7.84 (d, J=8.65 Hz, 1H)7.56 (dd, J=8.65, 1.86 Hz, 1H) 3.82-3.92 (m, 1H) 3.68-3.82 (m, 4H)3.08-3.27 (m, 1H) 2.58 (m, 4H) 2.31-2.49 (m, 4H). MS: (M+H)⁺=353/355.

Example 72BTrans-2-(3-morpholin-4-ylcyclobutyl)-6-pyrimidin-5-yl-1,3-benzothiazole

The title compound was prepared according to the procedure described inExample 1F, substituting the product of Example 72A for the product ofExample 1E. ¹H NMR (400 MHz, CDCl₃) δ ppm 9.24 (s, 1H) 8.99-9.05 (s, 2H)8.12 (d, J=8.59 Hz, 1H) 8.06 (d, J=1.23 Hz, 1H) 7.67 (dd, J=8.59, 1.84Hz, 1H) 3.86-3.97 (m, 1H) 3.71-3.82 (m, 4H) 3.15-3.24 (m, 1H) 2.35-2.67(m, 8H). MS: (M+H)⁺=353.

Example 73Trans-2-{3-[(2S)-2-(fluoromethyl)pyrrolidin-1-yl]cyclobutyl}-6-pyrimidin-5-yl-1,3-benzothiazoleExample 73ATrans-6-bromo-2-{3-[(2S)-2-(fluoromethyl)pyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazole

The title compound was prepared according to the procedure described inExample 43A, substituting S(+)-2-fluoromethylpyrrolidine(CAS#460748-85-0, prepared according to the procedure that described in:R. Altenbach et al., WO 2004043458) for 4-piperidinemethanol. ¹H NMR(300 MHz, CDCl₃) δ ppm 7.98 (d, J=1.70 Hz, 1H) 7.83 (d, J=8.81 Hz, 1H)7.56 (dd, J=8.65, 1.86 Hz, 1H) 4.30-4.46 (m, 1H) 4.14-4.29 (m, 1H)3.78-3.91 (m, 1H) 3.55-3.70 (m, 1H) 2.98-3.13 (m, 1H) 2.82-2.95 (m, 1H)2.53-2.72 (m, 4H) 2.39-2.50 (m, 1H) 1.70-1.97 (m, 2H) 1.50-1.59 (m, 2H).MS: (M+H)⁺=369/371.

Example 73BTrans-2-{3-[(2S)-2-(fluoromethyl)pyrrolidin-1-yl]cyclobutyl}-6-pyrimidin-5-yl-1,3-benzothiazole

The title compound was prepared according to the procedure described inExample 1F, substituting the product of Example 73A for the product ofExample 1E. ¹H NMR (300 MHz, CDCl₃) δ ppm 9.24 (s, 1H) 9.02 (s, 2H) 8.12(d, J=8.48 Hz, 1H) 8.06 (d, J=1.70 Hz, 1H) 7.67 (dd, J=8.48, 1.70 Hz,1H) 4.06-4.50 (m, 1H) 3.82-4.03 (m, 1H) 3.54-3.76 (m, 1H) 3.00-3.18 (m,1H) 2.79-2.95 (m, 1H) 2.55-2.74 (m, 3H) 2.34-2.54 (m, 1H) 1.70-1.97 (m,2H) 1.45-1.61 (m, 4H). MS: (M+H)⁺=369.

Example 74Trans-{(2S)-1-[3-(6-pyrimidin-5-yl-1,3-benzothiazol-2-yl)cyclobutyl]pyrrolidin-2-yl}methanolExample 74ATrans-{(2S)-1-[3-(6-bromo-1,3-benzothiazol-2-yl)cyclobutyl]pyrrolidin-2-yl}methanol

The title compound was prepared according to the procedure described inExample 43A, substituting S(+)-2-hydroxymethylpyrrolidine for4-piperidinemethanol. ¹H NMR (300 MHz, CDCl₃) δ ppm 7.99 (d, J=2.03 Hz,1H) 7.82 (d, J=8.48 Hz, 1H) 7.57 (dd, J=8.48, 2.03 Hz, 1H) 4.05-4.17 (m,1H) 3.28-3.95 (m, 5H) 2.51-2.87 (m, 4H) 1.70-2.18 (m, 4H) 1.41-1.65 (m,2H). MS: (M+H)⁺=367/369.

Example 74BTrans-{(2S)-1-[3-(6-pyrimidin-5-yl-1,3-benzothiazol-2-yl)cyclobutyl]pyrrolidin-2-yl}methanol

The title compound was prepared according to the procedure described inExample 1F, substituting the product of Example 74A for the product ofExample 1E. ¹H NMR (300 MHz, CDCl₃) δ ppm 9.24 (s, 1H) 9.02 (s, 2H) 8.11(d, J=8.48 Hz, 1H) 8.07 (d, J=2.03 Hz, 1H) 7.68 (dd, J=8.48, 1.70 Hz,1H) 3.89-4.04 (m, 1H) 3.55-3.74 (m, 2H) 3.26-3.47 (m, 1H) 2.62-2.88 (m,4H) 2.42-2.60 (m, 1H) 1.72-2.08 (m, 5H) 1.48-1.67 (m, 2H). MS:(M+H)⁺=367.

Example 75Trans-((2S)-1-{3-[6-(2,6-dimethylpyridin-3-yl)-1,3-benzothiazol-2-yl]cyclobutyl}pyrrolidin-2-yl)methanol

The title compound was prepared according to the procedure described inExample 1F, substituting the product of Example 74A for the product ofExample 1E and substituting the product of Example 2A forpyrimidine-5-boronic acid. ¹H NMR (300 MHz, CDCl₃) δ ppm 8.02 (d, J=8.81Hz, 1H) 7.77 (d, J=1.36 Hz, 1H) 7.45 (d, J=7.80 Hz, 1H) 7.40 (dd,J=8.48, 1.70 Hz, 1H) 7.07 (d, J=7.80 Hz, 1H) 3.83-4.00 (m, 1H) 3.52-3.75(m, 2H) 3.32-3.47 (m, 1H) 2.99-3.17 (m, 1H) 2.63-2.80 (m, 3H) 2.59 (s,3H) 2.50 (s, 3H) 1.70-2.08 (m, 5H) 1.46-1.65 (m, 2H). MS: (M+H)⁺=394.

Example 76Trans-2-[3-(2-methylpiperidin-1-yl)cyclobutyl]-6-pyrimidin-5-yl-1,3-benzothiazoleExample 76ATrans-6-bromo-2-[3-(2-methylpiperidin-1-yl)cyclobutyl]-1,3-benzothiazole

The title compound was prepared according to the procedure described inExample 43A, substituting 2-methylpiperidine (CAS # 109-05-7) for4-piperidinemethanol. ¹H NMR (300 MHz, CDCl₃) δ ppm 7.98 (d, J=1.70 Hz,1H) 7.83 (d, J=8.81 Hz, 1H) 7.56 (dd, J=8.65, 1.86 Hz, 1H) 3.78-3.90 (m,1H) 2.81-3.11 (m, 2H) 2.56-2.77 (m, 4H) 1.38-1.93 (m, 8H) 1.24 (s, 3H).MS: (M+H)⁺=365/367.

Example 76BTrans-2-[3-(2-methylpiperidin-1-yl)cyclobutyl]-6-pyrimidin-5-yl-1,3-benzothiazole

The title compound was prepared according to the procedure described inExample 1F, substituting the product of Example 76A for the product ofExample 1E. ¹H NMR (500 MHz, CDCl₃) δ ppm 9.24 (s, 1H) 8.99-9.04 (m, 2H)8.12 (d, J=8.24 Hz, 1H) 8.07 (d, J=1.83 Hz, 1H) 7.68 (dd, J=8.39, 1.68Hz, 1H) 3.78-3.90 (m, 1H) 3.51-3.67 (m, 1H) 2.53-2.80 (m, 5H) 1.61 (m,6H) 1.35-1.50 (m, 2H) 1.09 (s, 3H). MS: (M+H)⁺=365.

Example 77Trans-2-(3-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-ylcyclobutyl)-6-pyrimidin-5-yl-1,3-benzothiazoleExample 77A Trans-tert-butyl5-[3-(6-bromo-1,3-benzothiazol-2-yl)cyclobutyl]hexahydropyrrolo[3,4-b]pyrrole-1(2H)-carboxylate

The title compound was prepared according to the procedure described inExample 43A, substituting hexahydro-pyrrolo[3,4-b]pyrrole-1-carboxylicacid tert-butyl ester (prepared according to the procedure thatdescribed in: Q. Li et al., J. Med. Chem.; 39(16), 3070-3088, 1996) for4-piperidinemethanol. ¹H NMR (300 MHz, CDCl₃) δ ppm 7.97 (d, J=1.70 Hz,1H) 7.82 (d, J=8.81 Hz, 1H) 7.56 (dd, J=8.82, 2.03 Hz, 1H) 4.10-4.37 (m,2H) 3.85-4.02 (m, 1H) 3.49 (m 2H) 3.11-3.29 (m, 1H) 2.95-3.07 (m, 1H)2.79-2.94 (m, 1H) 2.31-2.67 (m, 6H) 1.90-2.11 (m, 1H) 1.65-1.86 (m, 1H)1.46 (s, 9H). MS: (M+H)⁺=478/480.

Example 77BTrans-tert-butyl5-[3-(6-pyrimidin-5-yl-1,3-benzothiazol-2-yl)cyclobutyl]hexahydropyrrolo[3,4-b]pyrrole-1(2H)-carboxylate

The title compound was prepared according to the procedure described inExample 1F, substituting the product of Example 77A for the product ofExample 1E. ¹H NMR (300 MHz, CDCl₃) δ ppm 9.23 (s, 1H) 9.01 (s, 2H) 8.11(d, J=8.48 Hz, 1H) 8.06 (d, J=1.36 Hz, 1H) 7.67 (dd, J=8.42, 1.87 Hz,1H) 4.15-4.30 (m, 1H) 3.91-4.06 (m, 2H) 3.43 (m, 3H) 3.12-3.26 (m, 1H)2.79-2.92 (m, 1H) 2.66-2.76 (m, 1H) 2.49-2.62 (m, 4H) 2.31-2.45 (m, 1H)1.90-2.08 (m, 1H) 1.67-1.83 (m, 1H) 1.44-1.47 (m, 9H). MS: (M+H)⁺=478.

Example 77CTrans-2-(3-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-ylcyclobutyl)-6-pyrimidin-5-yl-1,3-benzothiazole

The title compound was prepared according to the procedure described inExample 38C, substituting the product of Example 77B for the productExample 38B. ¹H NMR (300 MHz, CDCl₃) δ ppm 9.23 (s, 1H) 9.01 (s, 2H)8.11 (d, J=8.81 Hz, 1H) 8.05 (d, J=1.36 Hz, 1H) 7.66 (dd, J=8.48, 2.03Hz, 1H) 3.94-4.06 (m, 2H) 3.55-3.81 (m, 1H) 3.14-3.27 (m, 2H) 3.02-3.15(m, 1H) 2.75-2.96 (m, 3H) 2.45-2.68 (m, 6H) 1.96-2.13 (m, 1H) 1.67-1.82(m, 1H). MS: (M+H)⁺=378.

Example 78Trans-2-[3-(4-fluoropiperidin-1-yl)cyclobutyl]-6-pyrimidin-5-yl-1,3-benzothiazoleExample 78ATrans-6-bromo-2-[3-(4-fluoropiperidin-1-yl)cyclobutyl]-1,3-benzothiazole

The title compound was prepared according to the procedure described inExample 43A, substituting 4-fluoropiperidine hydrochloride (availablefrom ABCR) for 4-piperidinemethanol. ¹H NMR (300 MHz, CDCl₃) δ ppm 7.98(d, J=2.03 Hz, 1H) 7.83 (d, J=8.48 Hz, 1H) 7.56 (dd, J=8.48, 2.03 Hz,1H) 4.73 (m, 1H), 3.83 (m, 1H) 3.20 (m, 1H) 2.38-2.60 (m, 6H) 1.92 (m,4H) 1.59 (m, 2H). MS: (M+H)⁺=369/371.

Example 78BTrans-2-[3-(4-fluoropiperidin-1-yl)cyclobutyl]-6-pyrimidin-5-yl-1,3-benzothiazole

The title compound was prepared according to the procedure described inExample 1F, substituting the product of Example 78A for the product ofExample 1E. ¹H NMR (300 MHz, CDCl₃) δ ppm 9.24 (s, 1H) 9.00 (s, 2H) 8.11(d, J=8.48 Hz, 1H) 8.06 (d, J=1.70 Hz, 1H) 7.67 (dd, J=8.48, 1.70 Hz,1H) 4.65-4.80 (m, 1H) 3.89 (m, 1H) 3.20 (m, 1H) 2.36-2.63 (m, 8H) 1.93(m, 4H). MS: (M+H)⁺=369.

Example 79Trans-2-[3-(4-fluoropiperidin-1-yl)cyclobutyl]-6-(2-methoxypyrimidin-5-yl)-1,3-benzothiazole

The title compound was prepared according to the procedure described inExample 1F, substituting the product of Example 78A for the product ofExample 1E, and substituting 2-methoxypyrimidine-5-boronic acid forpyrimidine-5-boronic acid. ¹NMR (300 MHz, CDCl₃) δ ppm 8.78 (s, 2H) 8.07(d, J=8.48 Hz, 1H) 7.99 (d, J=1.70 Hz, 1H) 7.61 (dd, J=8.48, 1.70 Hz,1H) 4.71 (m, 1H) 4.09 (s, 3H) 3.90 (m, 1H) 3.23 (m, 1H) 2.62 (m, 6H)2.35 (m, 2H) 1.93 (m, 4H). MS: (M+H)⁺=399.

Example 80Trans-6-(2,6-dimethylpyridin-3-yl)-2-[3-(4-fluoropiperidin-1-yl)cyclobutyl]-1,3-benzothiazole

The title compound was prepared according to the procedure described inExample 1F, substituting the product of Example 78A for the product ofExample 1E, and substituting the product of Example 2A forpyrimidine-5-boronic acid. ¹H NMR (300 MHz, CDCl₃) δ ppm 8.02 (d, J=8.48Hz, 1H) 7.77 (d, J=1.70 Hz, 1H) 7.46 (d, J=7.80 Hz, 1H) 7.40 (dd,J=8.48, 1.70 Hz, 1H) 7.07 (d, J=7.80 Hz, 1H) 4.65-4.80 (m, 1H) 3.89 (m,1H) 3.21 (m, 1H) 2.36-2.63 (m, 8H) 2.59 (s, 3H) 2.50 (s, 3H) 1.86-2.05(m, 4H). MS: (M+H)⁺=396.

Example 81Trans-(3R)-1-[3-(6-pyrimidin-5-yl-1,3-benzothiazol-2-yl)cyclobutyl]piperidin-3-olExample 81A Cis-3-(6-pyrimidin-5-yl-1,3-benzothiazol-2-yl)cyclobutanol

The product of Example 1D (100 mg, 0.35 mmole), pyrimidine-5-boronicacid (65 mg, 0.53 mmole), dichlorobis(triphenylphosphine)palladium(II)(14.8 mg, 0.0021 mmole), 2-(dicyclohexyl-phosphino)biphenyl (7.4 mg,0.021 mmole), sodium carbonate (1 M solution, 0.53 ml, 0.53 mmole) and 2ml of ethanol/dioxane (1:1) were mixed under N₂ in a capped, sealedvial. The vial was sealed heated in the microwave for 10 minutes at 140°C. using a commercial microwave heating apparatus (i.e. the EmrysCreator). The reaction mixture was quenched with water and extractedwith dichloromethane (4×5 ml). The combined organic layers were washedwith brine, dried over sodium sulfate, filtered, and concentrated underreduced pressure to give the crude product which was purified by columnchromatography (10% methanol in dichloromethane) to give 80.4 mg (84.6%yield) of title compound. ¹H NMR (300 MHz, CDCl₃) δ ppm 9.25 (s, 1H),9.03 (s, 2H), 8.14 (d, J=8.48 Hz, 1H), 8.07 (d, J=1.70 Hz, 1H), 7.67(dd, J=8.48, 2.03 Hz, 1H), 4.40 (m, 1H), 3.50 (m, 1H), 3.01 (m, 2H),2.46 (m, 2H), 2.17 (brs, 1H). MS: (M+H)⁺=284.

Example 81BTrans-(3R)-1-[3-(6-pyrimidin-5-yl-1,3-benzothiazol-2-yl)cyclobutyl]piperidin-3-ol

The title compound was prepared according to the procedure described inExample 43A, substituting (R)-3-hydroxypiperidine hydrochloride (CAS#198976-43-1) for 4-piperidinemethanol and substituting Example 81A forExample 1D. ¹H NMR (300 MHz, CDCl₃) δ ppm 9.28 (s, 1H) 9.11 (s, 2H) 8.12(d, J=9.0 Hz, 1H) 8.10 (s, 1H) 7.71 (d, J=9.0 Hz, 1H) 4.28 (m, 1H) 3.96(m, 1H) 3.83 (m, 1H) 3.65 (m, 2H) 3.50 (m, 2H) 3.34-2.51 (m, 6H)2.60-1.07 (m, 4H). MS: (M+H)⁺=367.

Example 82Trans-N-ethyl-N-propyl-N-[3-(6-pyrimidin-5-yl-1,3-benzothiazol-2-yl)cyclobutyl]amine

The title compound was prepared according to the procedure described inExample 43A, substituting N-ethyl-N-propylamine for 4-piperidinemethanoland substituting Example 81A for Example 1D. ¹H NMR (300 MHz, CDCl₃) δppm 9.27 (s, 1H) 9.07 (s, 2H) 8.12 (d, J=9.0 Hz, 1H) 8.11 (s, 1H) 7.71(d, J=9.0 Hz, 1H) 4.14 (m, 1H) 4.00 (m, 1H) 3.22 (m, 1H) 3.10 (m, 2H)2.90-2.73 (m, 4H) 1.77 (m, 2H) 1.36 (t, 3H) 1.04 (t, 3H). MS:(M+H)⁺=353.

Example 83Trans-Diethyl-[3-(6-pyrimidin-5-yl-benzothiazol-2-yl)-cyclobutyl]-amineExample 83ATrans-[3-(6-Bromo-benzothiazol-2-yl)-cyclobutyl]-diethyl-amine

The title compound was prepared according to the procedure described inExample 43A, substituting diethylamine for 4-piperidinemethanol. 1H NMR(300 MHz, CHLOROFORM-D) δ ppm 7.98 (d, J=2.03 Hz, 1H), 7.83 (d, J=8.82Hz, 1H), 7.56 (dd, J=8.65, 1.86 Hz, 1H), 3.74-3.87 (m, 1H), 3.53-3.70(m, 1H), 2.45-2.82 (m, 6H) 1.56 (m, 2H) 1.00-1.17 (m, 6H).(M+H)⁺=341/343.

Example 83BTrans-Diethyl-[3-(6-pyrimidin-5-yl-benzothiazol-2-yl)-cyclobutyl]-amine

The title compound was prepared according to the procedure described inExample 81A, substituting Example 83A for Example 1D. 1H NMR (400 MHz,CHLOROFORM-D) δ ppm 9.23 (s, 1H), 9.01 (s, 2H), 8.12 (d, J=8.29 Hz, 1H),8.06 (d, J=1.84 Hz, 1H), 7.67 (dd, J=8.59, 1.84 Hz, 1H), 3.81-3.91 (m,1H), 3.55-3.68 (m, 1H), 2.57-2.75 (m, 8H), 1.06 (t, J=6.90 Hz, 6H). MS:(M+H)⁺=339.

Example 84Trans-Diethyl-{3-[6-(2-methoxy-pyrimidin-5-yl)-benzothiazol-2-yl]-cyclobutyl}-amine

The title compound was prepared according to the procedure described inExample 81A, substituting Example 83A for Example 1D, and substituting2-methoxypyrimidine-5-boronic acid for pyrimidine-5-boronic acid. 1H NMR(400 MHz, CHLOROFORM-D) d ppm 8.77 (s, 2H), 8.07 (d, J=8.29 Hz, 1H),7.98 (d, J=1.84 Hz, 1H), 7.60 (dd, J=8.44, 1.69 Hz, 1H), 4.09 (s, 3H),3.79-3.91 (m, 1H), 3.55-3.67 (m, 1H), 2.53-2.80 (m, 8H) 1.06 (t, J=6.90Hz, 6H). MS: (M+H)⁺=369.

Example 85Trans-{3-[6-(2-Methoxy-pyrimidin-5-yl)-benzothiazol-2-yl]-cyclobutyl}-methyl-propyl-amineExample 85ATrans-[3-(6-Bromo-benzothiazol-2-yl)-cyclobutyl]-methyl-propyl-amine

The title compound was prepared according to the procedure described inExample 43A, substituting N-methyl-N-propylamine for4-piperidinemethanol. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 7.97 (d,J=1.84 Hz, 1H), 7.82 (d, J=8.90 Hz, 1H), 7.55 (dd, J=8.75, 1.99 Hz, 1H),3.74-3.83 (m, 1H), 3.15-3.27 (m, 1H), 2.56 (t, J=7.06 Hz, 4H), 2.20-2.28(m, 2H), 2.16 (s, 3H), 1.46-1.56 (m, 2H), 0.91 (t, J=7.36 Hz, 3H). MS:(M+H)⁺=339/341.

Example 85BTrans-{3-[6-(2-Methoxy-pyrimidin-5-yl)-benzothiazol-2-yl]-cyclobutyl}-methyl-propyl-amine

The title compound was prepared according to the procedure described inExample 81A, substituting Example 85A for Example 1D, and substituting2-methoxypyrimidine-5-boronic acid for pyrimidine-5-boronic acid. 1H NMR(400 MHz, CHLOROFORM-D) δ ppm 8.77 (s, 2H), 8.07 (d, J=8.59 Hz, 1H),7.98 (d, J=1.84 Hz, 1H), 7.60 (dd, J=8.29, 1.84 Hz, 1H), 4.08 (s, 3H),3.80-3.90 (m, 1H), 3.22-3.32 (m, 1H), 2.57-2.66 (m, 4H), 2.24-2.32 (m,2H), 2.19 (s, 3H), 1.48-1.59 (m, 2H), 0.92 (t, J=7.36 Hz, 3H). MS:(M+H)⁺=369.

Example 86Trans-{3-[6-(2,6-Dimethyl-pyridin-3-yl)-benzothiazol-2-yl]-cyclobutyl}-methyl-propyl-amine

The title compound was prepared according to the procedure described inExample 81A, substituting Example 85A for Example 1D, and substitutingthe product of Example 2A for pyrimidine-5-boronic acid. 1H NMR (500MHz, CHLOROFORM-D) δ ppm 8.02 (d, J=8.54 Hz, 1H), 7.77 (d, J=1.22 Hz,1H), 7.46 (d, J=7.93 Hz, 1H), 7.40 (dd, J=8.24, 1.83 Hz, 1H), 7.07 (d,J=7.63 Hz, 1H), 3.82-3.91 (m, 1H), 3.27-3.41 (m, 1H), 2.68-2.77 (m, 2H),2.61-2.67 (m, 2H), 2.59 (s, 3H), 2.50 (s, 3H), 2.31-2.39 (m, 2H), 2.25(s, 3H), 1.53-1.63 (m, 2H), 0.94 (t, J=7.32 Hz, 3H). (M+H)⁺=366.

Example 87Trans-Methyl-{3-[6-(1-methyl-1H-pyrazol-4-yl)-benzothiazol-2-yl]-cyclobutyl}-propyl-amine

The title compound was prepared according to the procedure described inExample 81A, substituting Example 85A for Example 1D, and substituting1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(Available from Boron Molecular) for pyrimidine-5-boronic acid. 1H NMR(400 MHz, CHLOROFORM-D) δ ppm 7.94 (d, J=8.59 Hz, 1H), 7.92 (d, J=1.23Hz, 1H), 7.80 (s, 1H), 7.65 (s, 1H), 7.56 (dd, J=8.59, 1.84 Hz, 1H),3.97 (s, 3H), 3.79-3.89 (m, 1H), 3.26-3.42 (m, 1H), 2.56-2.78 (m, 4H),2.31-2.41 (m, 2H), 2.26 (s, 3H), 1.53-1.64 (m, 2H), 0.94 (t, J=7.36 Hz,3H). (M+H)⁺=341.

Example 88Trans-2-(Ethyl-{3-[6-(2-methoxy-pyrimidin-5-yl)-benzothiazol-2-yl]-cyclobutyl}-amino)-ethanolExample 88ATrans-2-{[3-(6-Bromo-benzothiazol-2-yl)-cyclobutyl]-ethyl-amino}-ethanol

The title compound was prepared according to the procedure described inExample 43A, substituting 2-(ethylamino)ethanol for4-piperidinemethanol. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 7.98 (d,J=2.15 Hz, 1H), 7.83 (d, J=8.59 Hz, 1H), 7.56 (dd, J=8.75, 1.99 Hz, 1H),3.72-3.80 (m, 1H), 3.62-3.71 (m, 1H), 3.58 (t, J=5.37 Hz, 2H), 2.53-2.68(m, 8H), 1.03 (t, J=7.06 Hz, 3H). (M+H)⁺=355/357.

Example 88BTrans-2-(Ethyl-{3-[6-(2-methoxy-pyrimidin-5-yl)-benzothiazol-2-yl]-cyclobutyl}-amino)-ethanol

The title compound was prepared according to the procedure described inExample 81A, substituting Example 88A for Example 1D, and substituting2-methoxypyrimidine-5-boronic acid for pyrimidine-5-boronic acid. 1H NMR(400 MHz, CHLOROFORM-D) δ ppm 8.77 (s, 2H), 8.07 (d, J=8.29 Hz, 1H),7.98 (d, J=1.53 Hz, 1H), 7.60 (dd, J=8.29, 1.84 Hz, 1H), 4.09 (s, 3H),3.78-3.88 (m, 1H), 3.65-3.76 (m, 1H), 3.60 (t, J=5.52 Hz, 2H), 2.53-2.71(m, 8H), 1.05 (t, J=7.21 Hz, 3H). MS: (M+H)⁺=385.

Example 89Trans-2-({3-[6-(2,6-Dimethyl-pyridin-3-yl)-benzothiazol-2-yl]-cyclobutyl}-ethyl-amino)-ethanol

The title compound was prepared according to the procedure described inExample 81A, substituting Example 88A for Example 1D, and substitutingthe product of Example 2A for pyrimidine-5-boronic acid. 1H NMR (500MHz, CHLOROFORM-D) δ ppm 8.02 (d, J=8.54 Hz, 1H), 7.77 (d, J=1.22 Hz,1H), 7.46 (d, J=7.63 Hz, 1H), 7.41 (dd, J=8.24, 1.53 Hz, 1H), 7.07 (d,J=7.93 Hz, 1H), 3.78-3.90 (m, 2H), 3.71 (t, J=5.03 Hz, 2H), 2.79-2.88(m, 4H), 2.75-2.79 (m, 2H), 2.65-2.71 (m, 2H), 2.59 (s, 3H), 2.50 (s,3H), 1.14 (t, J=7.17 Hz, 3H). MS: (M+H)⁺=382.

Example 906-Pyrimidin-5-yl-2-(3-pyrrolidin-1-ylmethyl-cyclobutyl)-benzothiazoleExample 90A [3-(6-Bromo-benzothiazol-2-yl)-cyclobutyl]-methanol

The product of Example 1B (600.0 mg, 2.14 mmole) was dissolved in 4 mlof THF and cooled to 0° C. BH₃.THF (1 M in THF, 5.35 ml, 5.35 mmole) wasadded to it and the mixture was allowed to warm to room temperature andstirred for 2 hours. The mixture was cooled to 0° C., 30% H₂O₂ (2.5 ml)and 3M NaOH were successively added dropwise. The mixture was slowlywarmed to room temperature and stirred for 5 hours. The mixture wasquenched with brine, and extracted three times with dichloromethane. Thecombined organics were washed with sodium bisulfite and brine, driedover sodium sulfate, filtered and concentrated to the crude product,which was purified by chromatography (5% methanol in dichloromethane) toprovide the title compound (268.9 mg, 42.1%). ¹H NMR (300 MHz, CDCl₃)7.98 (d, J=2.0 Hz, 1H) 7.83 (d, J=8.8 Hz, 1H) 7.56 (dd, J=8.7, 1.9 Hz,1H) 3.79 (m, 2H) 3.66 (m, 1H) 2.55-2.70 (m, 3H) 2.42 (m, 1H) 2.26 (m,1H). MS: (M+H)⁺=298/300.

Example 90B 6-Bromo-2-(3-pyrrolidin-1-ylmethyl-cyclobutyl)-benzothiazole

The title compound was prepared according to the procedure described inExample 43A, except for substituting pyrrolidine for4-piperidinemethanol and substituting Example 90A for Example 1D. ¹H NMR(300 MHz, CDCl₃) δ ppm 7.98 (d, J=2.03 Hz, 1H) 7.82 (d, J=8.48 Hz, 1H)7.56 (dd, J=8.48, 2.03 Hz, 1H) 3.81-3.94 (m, 3H) 3.25-3.35 (m, 3H)2.76-2.92 (m, 4H) 2.09-2.57 (m, 6H). MS: (M+H)⁺=351/353.

Example 90C6-Pyrimidin-5-yl-2-(3-pyrrolidin-1-ylmethyl-cyclobutyl)-benzothiazole

The title compound was prepared according to the procedure described inExample 1F, except for substituting the product of Example 90B for theproduct of Example 1E. MS: (M+H)⁺=351.

Example 91Trans-5-(2,6-Dimethyl-pyridin-3-yl)-2-[3-(2-methyl-pyrrolidin-1-yl)-cyclobutyl]-benzothiazoleExample 91A 2-Amino-4-chloro-benzenethiol

The title compound was prepared according to the procedure described inExample 1A, substituting 5-chloro-2-benzothiazolinone for6-bromo-2-benzothiazolinone. 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 7.03(d, J=8.48 Hz, 1H), 6.71 (d, J=2.03 Hz, 1H), 6.56 (dd, J=8.31, 2.20 Hz,1H), 4.43 (br, 2H). MS: (M+H)⁺=160, (M+H)⁺=316 (dimmer).

Example 91B 5-Chloro-2-(3-methylene-cyclobutyl)-benzothiazole

The title compound was prepared according to the procedure described inExample 1B, substituting 91A for 1A (42% yield). 1H NMR (500 MHz,CHLOROFORM-D) δ ppm 7.96 (d, J=2.18 Hz, 1H), 7.75 (d, J=8.42 Hz, 1H),7.33 (dd, J=8.58, 2.03 Hz, 1H), 4.88-4.95 (m, 1H), 4.76-4.82 (m, 1H),3.90-4.00 (m, 1H), 3.14-3.30 (m, 2H), 2.90-3.12 (m, 2H). (M+H)⁺=236.

Example 91C 3-(5-Chloro-benzothiazol-2-yl)-cyclobutanone

The title compound was prepared according to the procedure described inExample 1C, substituting 91B for 1B (46% yield). 1H NMR (500 MHz,CHLOROFORM-D) δ ppm 7.99 (d, J=1.87 Hz, 1H), 7.77 (d, J=8.42 Hz, 1H),7.37 (dd, J=8.58, 2.03 Hz, 1H), 4.00-4.11 (m, 1H), 3.56-3.75 (m, 4H).(M+H)⁺=238.

Example 91D Cis-3-(5-chloro-benzothiazol-2-yl)-cyclobutanol

The title compound was prepared according to the procedure described inExample 1D, substituting 91C for 1C. Crude product was used in the nextstep without purification.

Example 91ETrans-5-Chloro-2-[3-(2-methyl-pyrrolidin-1-yl)-cyclobutyl]-benzothiazole

The title compound was prepared according to the procedure described inExample 1E, substituting 91 D for 1 D. 1H NMR (500 MHz, CHLOROFORM-D) δppm 7.98 (d, J=1.83 Hz, 1H), 7.75 (d, J=8.54 Hz, 1H), 7.33 (dd, J=8.54,2.14 Hz, 1H), 3.78-3.88 (m, 1H), 3.44-3.56 (m, 1H), 3.01-3.11 (m, 1H),2.62-2.81 (m, 3H), 2.44-2.58 (m, 2H), 2.25-2.37 (m, 1H), 1.91-2.01 (m,1H), 1.78-1.88 (m, 1H), 1.67-1.76 (m, 1H), 1.43-1.54 (m, 1H), 1.13 (d,J=5.80 Hz, 3H). (M+H)⁺=307.

Example 91FTrans-5-(2,6-Dimethyl-pyridin-3-yl)-2-[3-(2-methyl-pyrrolidin-1-yl)-cyclobutyl]-benzothiazole

In a 4 ml vial, the product of Example 91E (30 mg, 0.098 mmole),potassium fluoride (19 mg, 0.323 mmole) andtris(dibenzylideneacetone)dipalladium (5.3 mg, 0.0075 mmole) werecharged and dried on high vacuum for 30 min. The product of Example 2A(34 mg, 0.147 mmole) was added followed by dioxane (1 ml) under nitrogenatmosphere. Tri-t-butylphosphine (10 wt % in hexane, 45 ul, 0.0147mmole) was added last and the vial was sealed and heated at 85° C.overnight then 95° C. for 7 h. TLC (TLC conditions: 1% ammoniumhydroxide and 10% methanol in dichloromethane on silica gel) showed anew spot besides the starting material. The reaction mixture wasquenched with water and extracted three times with dichloromethane. Thecombined organic layers were washed with brine, dried over sodiumsulfate, filtered, and concentrated. The crude product was purified bycolumn chromatography (eluted by 0.35% ammonium hydroxide and 3.5%methanol in dichloromethane) to give 6 mg (16% yield) of title compound.1H NMR (300 MHz, CHLOROFORM-D) δ ppm 7.93 (d, J=1.36 Hz, 1H), 7.89 (d,J=8.14 Hz, 1H), 7.47 (d, J=7.80 Hz, 1H), 7.30 (dd, J=8.48, 1.70 Hz, 1H),7.08 (d, J=7.80 Hz, 1H), 3.80-3.94 (m, 1H), 3.46-3.60 (m, 1H), 3.02-3.15(m, 1H), 2.66-2.84 (m, 3H), 2.60-2.61 (s, 3H), 2.50-2.54 (s, 3H),2.26-2.40 (m, 2H), 1.62-2.04 (m, 4H), 1.43-1.58 (m, 1H), 1.15 (d, J=5.76Hz, 3H). (M+H)⁺=378.

Example 92Trans-5-(2,4-Dimethoxy-pyrimidin-5-yl)-2-[3-(2-methyl-pyrrolidin-1-yl)-cyclobutyl]-benzothiazole

The title compound was prepared according to the procedure described inExample 91F, substituting 2,6-dimethoxy-5-pyrimidineboronic acid forExample 2A. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 8.34 (s, 1H), 8.13 (s,1H), 7.89 (d, J=8.29 Hz, 1H), 7.48 (dd, J=8.29, 1.84 Hz, 1H), 4.06 (s,3H), 4.05 (s, 3H), 3.81-3.92 (m, 1H), 3.46-3.61 (m, 1H), 2.99-3.17 (m,1H), 2.63-2.86 (m, 3H), 2.48-2.62 (m, 2H), 2.27-2.41 (m, 1H), 1.45-2.03(m, 4H), 1.14 (s, 3H). (M+H)⁺=411.

Example 93Trans-6-(1-Methyl-1H-pyrazol-4-yl)-2-[3-(2-methyl-pyrrolidin-1-yl)-cyclobutyl]-benzothiazole

The title compound was prepared according to the procedure described inExample 51A-C, substituting Example 1E for Example 44A. 1H NMR (400 MHz,CHLOROFORM-D) d ppm 7.90-7.98 (m, 2H) 7.80 (s, 1H) 7.65 (s, 1H) 7.56(dd, J=8.44, 1.69 Hz, 1H) 3.97 (s, 3H) 3.80-3.92 (m, 1H) 3.50-3.63 (m,1H) 3.01-3.22 (m, 1H) 2.67-2.89 (m, 2H) 2.50-2.64 (m, 2H) 2.31-2.45 (m,1H) 1.93-2.04 (m, 1H) 1.81-1.91 (m, 1H) 1.65-1.81 (m, 2H) 1.46-1.58 (m,1H) 1.17 (d, J=4.60 Hz, 3H). (M+H)⁺=353.

Example 94Trans-2-[3-(4-Fluoro-piperidin-1-yl)-cyclobutyl]-6-(1-methyl-1H-pyrazol-4-ylbenzothiazole

The title compound was prepared according to the procedure described inExample 51A-C, substituting Example 78A for Example 44A. 1H NMR (400MHz, CHLOROFORM-D) d ppm 7.88-7.98 (m, 2H) 7.80 (s, 1H) 7.65 (s, 1H)7.56 (d, J=8.29 Hz, 1H) 4.60-4.80 (m, 1H) 3.97 (s, 3H) 3.76-3.89 (m, 1H)3.11-3.24 (m, 1H) 2.44-2.65 (m, 5H) 2.25-2.39 (m, 2H) 1.80-2.04 (m, 3H)1.52-1.62 (m, 2H). (M+H)⁺=371.

Example 95Trans-2-(3-azetidin-1-ylcyclobutyl)-6-(2-methoxypyrimidin-5-yl)-1,3-benzothiazole

The title compound was prepared according to the procedure described inExample 1F, except for substituting the product of Example 61A for theproduct of Example 1E, and substituting 2-methoxypyrimidine-5-boronicacid (Frontier Scientific, Inc., Logan, Utah, USA) forpyrimidine-5-boronic acid. 1H NMR (300 MHz, CDCl₃) δ ppm 8.77 (s, 2H)8.07 (d, J=8.48 Hz, 1H) 7.97 (d, J=2.03 Hz, 1H) 7.59 (dd, J=8.48, 2.03Hz, 1H) 4.08 (s, 3H) 3.93-4.06 (m, 1H) 3.18-3.34 (m, 5 H) 2.49-2.61 (m,1H) 2.34-2.47 (m, 3H) 2.03-2.19 (m, 2H). MS: (M+H)⁺=353.

Example 96Trans-2-(3-azetidin-1-ylcyclobutyl)-6-(2,6-dimethylpyridin-3-yl)-1,3-benzothiazole

The title compound was prepared according to the procedure described inExample 1F, except for substituting the product of Example 61A for theproduct of Example 1E, and substituting Example 2A(2,6-dimethyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine)for pyrimidine-5-boronic acid. ¹H NMR (300 MHz, CDCl₃) δ ppm 8.01 (d,J=8.48 Hz, 1H) 7.75 (d, J=1.36 Hz, 1H) 7.45 (d, J=7.80 Hz, 1H) 7.39 (dd,J=8.48, 1.70 Hz, 1H) 7.06 (d, J=7.80 Hz, 1H) 3.96-4.08 (m, 1H) 3.19-3.40(m, 5H) 2.59 (s, 3H) 2.49 (s, 3H) 2.37-2.56 (m, 4H) 2.07-2.19 (m, 2H).MS: (M+H)⁺=350.

Example 97Trans-2-(3-azetidin-1-ylcyclobutyl)-6-(1-methyl-1H-pyrazol-4-yl)-1,3-benzothiazole

The title compound was prepared according to the procedure described inExample 1F, except for substituting the product of Example 61A for theproduct of Example 1E, and substituting 1-methyl-1H-pyrazoleboronic acidpinacol ester for pyrimidine-5-boronic acid. ¹H NMR (300 MHz, CDCl₃) δppm 7.89-7.97 (m, 2H) 7.80 (s, 1H) 7.65 (s, 1H) 7.55 (dd, J=8.31, 1.86Hz, 1H) 3.97 (s, 3H) 3.92-4.07 (m, 1H) 3.21-3.45 (m, 5H) 2.36-2.62 (m,4H) 2.06-2.24 (m, 2H). MS: (M+H)⁺=325.

Example 98Trans-2-(3-azepan-1-ylcyclobutyl)-6-(2-methoxypyrimidin-5-yl)-1,3-benzothiazole

The title compound was prepared according to the procedure described inExample 1F, except for substituting the product of Example 71A for theproduct of Example 1E, and substituting 2-methoxypyrimidine-5-boronicacid (Frontier Scientific, Inc., Logan, Utah, USA) forpyrimidine-5-boronic acid. ¹H NMR (500 MHz, CDCl₃) δ ppm 8.78 (s, 2H)8.07 (d, J=8.24 Hz, 1H) 7.98 (d, J=1.83 Hz, 1H) 7.59 (dd, J=8.39, 1.68Hz, 1H) 4.09 (s, 3H) 3.78-3.86 (m, 1H) 3.33-3.44 (m, 1H) 2.45-2.65 (m,8H) 1.58-1.75 (m, 8H). MS: (M+H)⁺=395.

Example 99Trans-2-(3-azepan-1-ylcyclobutyl)-6-(2,6-dimethylpyridin-3-yl)-1,3-benzothiazole

The title compound was prepared according to the procedure described inExample 1F, except for substituting the product of Example 71A for theproduct of Example 1E, and substituting Example 2A(2,6-dimethyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine)for pyrimidine-5-boronic acid. ¹H NMR (500 MHz, CDCl₃) δ ppm 8.02 (d,J=8.54 Hz, 1H) 7.76 (d, J=1.53 Hz, 1H) 7.46 (d, J=7.63 Hz, 1H) 7.39 (dd,J=8.24, 1.83 Hz, 1H) 7.07 (d, J=7.63 Hz, 1H) 3.78-3.86 (m, 1H) 3.32-3.43(m, 1H) 2.59 (s, 6H) 2.45-2.56 (m, 8H) 1.58-1.73 (m, 8H). MS:(M+H)⁺=392.

Example 100Trans-2-(3-azepan-1-ylcyclobutyl)-6-(1-methyl-1H-pyrazol-4-yl)-1,3-benzothiazole

The title compound was prepared according to the procedure described inExample 1F, except for substituting the product of Example 71A for theproduct of Example 1E, and substituting 1-methyl-4-1H-pyrazoleboronicacid pinacol ester for pyrimidine-5-boronic acid. ¹H NMR (500 MHz,CDCl₃) δ ppm 7.89-7.97 (m, 2H) 7.80 (s, 1H) 7.65 (s, 1H) 7.55 (dd,J=8.39, 1.68 Hz, 1H) 3.97 (s, 3H) 3.74-3.83 (m, 1H) 3.30-3.41 (m, 1H)2.46-2.61 (m, 8H) 1.56-1.71 (m, 8H). MS: (M+H)⁺=367.

Example 101Cis-N-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-acetamideExample 101A Cis-2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-ylamine

The product of Example 44A(trans-6-bromo-2-(3-piperidin-1-ylcyclobutyl)-1,3-benzothiazole) (658mg, 1.875 mmole), tris(dibenzylideneacetone)dipalladium (0) (34 mg,0.037 mmole), racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl(BINAP, 70 mg, 0.113 mmole) and sodium tert-butoxide (249 mg, 2.62mmole) were charged in a tube and sealed. The system was vacuumed for 2hours and refilled with nitrogen. Toluene (10 mL) was added followed bybenzophenone imine (409 mg, 377 μl, 2.25 mmole). The sealed tube washeated in an oil bath (temp 95° C.) for 18 hours. TLC (TLC conditions:0.5% ammonium hydroxide and 5% methanol in dichloromethane on silicagel) confirmed the completion of the reaction with two new spots. Thereaction was quenched with water and the mixture was extracted threetimes with dichloromethane. The organic layers were dried (over Na₂SO₄),filtered and concentrated under reduced pressure to give the crudeproduct as the benzophenone imine. The crude product was dissolved intetrahydrofuran (10 mL) and 2N HCl (4 mL). The mixture was stirred atroom temperature for 2 hours. TLC (TLC conditions: 0.5% ammoniumhydroxide and 5% methanol in dichloromethane on silica gel) indicatedcomplete conversion of the starting material (imine) to two newproducts. The mixture was basified with 2N NaOH (6 mL) and extractedthree times with dichloromethane. The organic layers were dried (overNa₂SO₄), filtered and concentrated under reduced pressure to give thecrude product. The crude product was purified by column chromatography(0.4% ammonium hydroxide and 4% methanol in dichloromethane). Theproduct with a Rf value of 0.3 (TLC conditions: 0.5% ammonium hydroxideand 5% methanol in dichloromethane on silica gel) corresponded to thecis-product (270 mg). ¹H NMR (300 MHz, CDCl₃) δ ppm 7.71 (d, J=8.82 Hz,1H) 7.08 (d, J=2.03 Hz, 1H) 6.79 (dd, J=8.82, 2.37 Hz, 1H) 3.75 (s, 2H)3.42-3.57 (m, 1H) 2.68-2.82 (m, 1H) 2.55-2.69 (m, 2H) 2.16-2.39 (m, 6H)1.52-1.65 (m, 4H) 1.39-1.51 (m, 2H). MS: (M+H)⁺=288.

Example 101BTrans-2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-ylamine

In the above preparation, the product with a Rf value of 0.2 (TLCconditions: 0.5% ammonium hydroxide and 5% methanol in dichloromethaneon silica gel) corresponded to the trans-isomer (100 mg). ¹H NMR (300MHz, CDCl₃) δ ppm 7.74 (d, J=8.82 Hz, 1H) 7.09 (d, J=2.37 Hz, 1H) 6.80(dd, J=8.65, 2.20 Hz, 1H) 3.67-3.83 (m, 3H) 2.99-3.15 (m, 1H) 2.46-2.60(m, 4H) 2.21-2.38 (m, 4H) 1.53-1.68 (m, 4H) 1.39-1.51 (m, 2H). MS:(M+H)⁺=288.

Example 101CCis-N-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-acetamide

The product of Example 101A (20 mg, 0.070 mmole) was dissolved inanhydrous dichloromethane (1.5 mL). To the solution was addedtriethylamine (35.6 mg, 49 μL, 0.35 mmole) and acetyl chloride (10 μL,0.14 mmole). The mixture was stirred at room temperature overnight thendiluted with water. The aqueous layer was extracted three times withdichloromethane and the combined organic layers were concentrated togive the crude product. The crude product was purified by columnchromatography (0.5% ammonium hydroxide and 5% methanol indichloromethane) to give the title compound. ¹H NMR (500 MHz, CDCl₃) δppm 8.39 (d, J=2.14 Hz, 1H) 7.84 (d, J=8.54 Hz, 1H) 7.37 (s, 1H) 7.22(dd, J=8.85, 2.14 Hz, 1H) 3.48-3.59 (m, 1H) 2.72-2.83 (m, 1H) 2.60-2.70(m, 2H) 2.24-2.39 (m, 6H) 2.21 (s, 3H) 1.54-1.64 (m, 4H) 1.40-1.51 (m,2H). MS: (M+H)⁺=330.

Example 102Cis-2-Chloro-N-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-acetamide

The title compound was prepared according to the procedure described inExample 101C, except for substituting chloroacetyl chloride for acetylchloride. ¹H NMR (500 MHz, CDCl₃) δ ppm 8.38 (d, J=1.83 Hz, 1H) 8.36 (s,1H) 7.90 (d, J=8.85 Hz, 1H) 7.35 (dd, J=8.85, 2.14 Hz, 1H) 4.23 (s, 2H)3.49-3.61 (m, 1H) 2.74-2.84 (m, 1H) 2.61-2.72 (m, 2H) 2.20-2.41 (m, 6H)1.54-1.63 (m, 4H) 1.40-1.52 (m, 2H). MS: (M+H)⁺=364.

Example 103Cis-N-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-propionamide

The title compound was prepared according to the procedure described inExample 101C, except for substituting propionyl chloride for acetylchloride. ¹H NMR (500 MHz, CDCl₃) δ ppm 8.43 (s, 1H) 7.84 (d, J=8.54 Hz,1H) 7.30 (d, 1H) 7.23 (dd, J=8.54, 2.14 Hz, 1H) 3.48-3.60 (m, 1H)2.72-2.84 (m, 1H) 2.61-2.70 (m, 2H) 2.43 (q, J=7.53 Hz, 2H) 2.22-2.38(m, 6H) 1.54-1.64 (m, 4H) 1.39-1.51 (m, 2H) 1.27 (t, J=7.63 Hz, 3H). MS:(M+H)⁺=344.

Example 104Cis-N-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-isobutyramide

The title compound was prepared according to the procedure described inExample 101C, except for substituting isobutyryl chloride for acetylchloride. ¹H NMR (500 MHz, CDCl₃) δ ppm 8.46 (d, J=1.83 Hz, 1H) 7.85 (d,J=8.54 Hz, 1H) 7.29 (s, 1H) 7.23 (dd, J=8.85, 2.14 Hz, 1H) 3.48-3.58 (m,1H) 2.71-2.82 (m, 1H) 2.61-2.70 (m, 2H) 2.48-2.59 (m, 1H) 2.22-2.39 (m,6H) 1.54-1.64 (m, 4H) 1.39-1.51 (m, 2H) 1.28 (d, J=7.02 Hz, 6H). MS:(M+H)⁺=358.

Example 105 Cis-Cyclopropanecarboxylicacid[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-amide

The title compound was prepared according to the procedure described inExample 101C, except for substituting cyclopropane carbonyl chloride foracetyl chloride. 1H NMR (500 MHz, CDCl₃) δ ppm 8.42 (s, 1H) 7.84 (d,J=8.54 Hz, 1H) 7.56 (s, 1H) 7.24 (dd, J=8.70, 1.98 Hz, 1H) 3.48-3.58 (m,1H) 2.73-2.81 (m, 1H) 2.60-2.70 (m, 2H) 2.23-2.39 (m, 6H) 1.56-1.64 (m,4H) 1.49-1.56 (m, 1H) 1.40-1.49 (m, 2H) 1.08-1.15 (m, 2H) 0.83-0.91 (m,2H). MS: (M+H)⁺=356.

Example 106 Cis-Cyclobutanecarboxylicacid[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-amide

The title compound was prepared according to the procedure described inExample 101C, except for substituting cyclobutane carbonyl chloride foracetyl chloride. ¹H NMR (500 MHz, CDCl₃) δ ppm 8.46 (d, J=2.14 Hz, 1H)7.84 (d, J=8.85 Hz, 1H) 7.22 (dd, J=8.54, 2.14 Hz, 1H) 7.15 (s, 1H)3.48-3.60 (m, 1H) 3.13-3.23 (m, 1H) 2.72-2.83 (m, 1H) 2.61-2.70 (m, 2H)2.37-2.46 (m, 2H) 2.19-2.36 (m, 8H) 1.89-2.09 (m, 2H) 1.54-1.64 (m, 4H)1.40-1.50 (m, J=4.88 Hz, 2H). MS: (M+H)⁺=370.

Example 107 Cis-Cyclopentanecarboxylicacid[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-amide

The title compound was prepared according to the procedure described inExample 101C, except for substituting cyclopentane carbonyl chloride foracetyl chloride. ¹H NMR (500 MHz, CDCl₃) δ ppm 8.46 (d, J=2.14 Hz, 1H)7.84 (d, J=8.54 Hz, 1H) 7.32 (s, 1H) 7.22 (dd, J=8.85, 2.14 Hz, 1H)3.48-3.60 (m, 1H) 2.61-2.83 (m, 4H) 2.22-2.40 (m, 6H) 1.87-2.01 (m, 4H)1.78-1.86 (m, 2H) 1.55-1.68 (m, 6H) 1.40-1.50 (m, 2H). MS: (M+H)⁺=384.

Example 108 Cis-Cyclohexanecarboxylicacid[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-amide

The title compound was prepared according to the procedure described inExample 101C, except for substituting cyclohexane carbonyl chloride foracetyl chloride. ¹H NMR (500 MHz, CDCl₃) δ ppm 8.46 (d, J=1.83 Hz, 1H)7.84 (d, J=8.85 Hz, 1H) 7.30 (s, 1H) 7.22 (dd, J=8.54, 2.14 Hz, 1H)3.47-3.59 (m, 1H) 2.72-2.81 (m, 1H) 2.61-2.70 (m, 2H) 2.21-2.40 (m, 6H)1.93-2.02 (m, 2H) 1.82-1.90 (m, 2H) 1.67-1.74 (m, 1H) 1.52-1.64 (m, 6H)1.40-1.50 (m, 2H) 1.21-1.40 (m, 4H). MS: (M+H)⁺=384.

Example 109 Cis-Furan-2-carboxylicacid[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-amide

The title compound was prepared according to the procedure described inExample 101C, except for substituting 2-furoyl chloride for acetylchloride. ¹H NMR (500 MHz, CDCl₃) δ ppm 8.53 (d, J=2.14 Hz, 1H) 8.19 (s,1H) 7.90 (d, J=8.54 Hz, 1H) 7.54 (s, 1H) 7.40 (dd, J=8.70, 2.29 Hz, 1H)7.24-7.31 (m, 1H) 6.58 (dd, J=3.51, 1.68 Hz, 1H) 3.50-3.62 (m, 1H)2.74-2.83 (m, 1H) 2.61-2.71 (m, 2H) 2.24-2.41 (m, 6H) 1.55-1.64 (m, 4H)1.41-1.51 (m, 2H). MS: (M+H)⁺=382.

Example 110Cis-4-Cyano-N-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-benzamide

The title compound was prepared according to the procedure described inExample 101C, except for substituting 4-cyanobenzoyl chloride for acetylchloride. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.50 (d, J=2.15 Hz, 1H)7.96-8.02 (m, 3H) 7.92 (d, J=8.59 Hz, 1H) 7.81 (d, J=8.59 Hz, 2H) 7.39(dd, J=8.75, 2.30 Hz, 1H) 3.49-3.62 (m, 1H) 2.73-2.85 (m, 1H) 2.62-2.73(m, 2H) 2.24-2.38 (m, 6H) 1.54-1.64 (m, 4H) 1.41-1.51 (m, 2H). MS:(M+H)⁺=417.

Example 111Cis-4-Cyano-N-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-benzenesulfonamide

The title compound was prepared according to the procedure described inExample 101C, except for substituting 4-cyanobenzenesulfonyl chloridefor acetyl chloride. ¹H NMR (500 MHz, CDCl₃) δ ppm 8.07 (d, J=8.54 Hz,2H) 7.94 (d, J=8.54 Hz, 1H) 7.87-7.91 (m, 3H) 7.51 (d, J=2.14 Hz, 1H)7.02 (dd, J=8.54, 2.14 Hz, 1H) 3.57-3.64 (m, 1H) 2.76-2.86 (m, 1H)2.64-2.75 (m, 2H) 2.24-2.41 (m, 6H) 1.56-1.65 (m, 4H) 1.41-1.51 (m, 2H).MS: (M+H)⁺=453.

Example 112 Cis-Thiophene-2-sulfonicacid-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-amide

The title compound was prepared according to the procedure described inExample 101C, except for substituting thiophene-2-sulfonyl chloride foracetyl chloride. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.91 (d, J=8.85 Hz, 1H)7.79 (dd, J=3.97, 1.22 Hz, 1H) 7.75 (dd, J=5.03, 1.37 Hz, 1H) 7.63 (d,J=2.14 Hz, 1H) 7.16 (dd, J=5.03, 3.81 Hz, 2H) 7.12 (dd, J=8.54, 2.14 Hz,1H) 3.53-3.64 (m, 1H) 2.75-2.83 (m, 1H) 2.62-2.73 (m, 2H) 2.23-2.39 (m,6H) 1.55-1.63 (m, 4H) 1.40-1.51 (m, 2H). MS: (M+H)⁺=434.

Example 113 Cis-Thiophene-2-carboxylicacid-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-amide

The title compound was prepared according to the procedure described inExample 101C, except for substituting 2-thiophene carbonyl chloride foracetyl chloride. ¹H NMR (500 MHz, CDCl₃) δ ppm 8.49 (d, J=2.14 Hz, 1H)7.90 (d, J=8.54 Hz, 1H) 7.81 (s, 1H) 7.63-7.69 (m, 1H) 7.55-7.59 (m, 1H)7.37 (dd, J=8.54, 2.14 Hz, 1H) 7.15 (dd, J=5.03, 3.81 Hz, 1H) 3.50-3.60(m, 1H) 2.73-2.83 (m, 1H) 2.61-2.72 (m, 2H) 2.23-2.39 (m, 6H) 1.55-1.63(m, 4H) 1.41-1.50 (m, 2H). MS: (M+H)⁺=398.

Example 114 Cis-Thiophene-2-carboxylicacid-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-amide

The title compound was prepared according to the procedure described inExample 101C, except for substituting 2-thiophene acetyl chloride foracetyl chloride. ¹H NMR (500 MHz, CDCl₃) δ ppm 8.33 (d, J=1.83 Hz, 1H)7.82 (d, J=8.54 Hz, 1H) 7.44 (s, 1H) 7.33 (dd, J=4.58, 1.83 Hz, 1H) 7.15(dd, J=8.54, 2.14 Hz, 1H) 7.01-7.09 (m, 2H) 3.98 (s, 2H) 3.47-3.58 (m,1H) 2.71-2.82 (m, 1H) 2.64 (m, 2H) 2.21-2.38 (m, 6H) 1.52-1.65 (m, 4H)1.45 (s, 2H). MS: (M+H)⁺=412.

Example 115Cis-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-carbamic acidisobutyl ester

The title compound was prepared according to the procedure described inExample 101C, except for substituting isobutylchloroformate for acetylchloride. ¹H NMR (500 MHz, CDCl₃) δ ppm 8.18 (s, 1H) 7.84 (d, J=8.54 Hz,1H) 7.19 (dd, J=8.85, 2.14 Hz, 1H) 6.72 (s, 1H) 3.98 (d, J=6.71 Hz, 2H)3.48-3.59 (m, 1H) 2.72-2.82 (m, 1H) 2.61-2.70 (m, 2H) 2.22-2.38 (m, 6H)1.94-2.05 (m, 1H) 1.54-1.64 (m, 4H) 1.41-1.51 (m, 2H) 0.98 (d, J=6.71Hz, 6H). MS: (M+H)⁺=388.

Example 116 Cis-Morpholine-4-carboxylicacid-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-amide

The title compound was prepared according to the procedure described inExample 101C, except for substituting 4-morpholine carbonyl chloride foracetyl chloride. ¹H NMR (500 MHz, CDCl₃) δ ppm 8.15 (d, J=2.14 Hz, 1H)7.82 (d, J=8.85 Hz, 1H) 7.17 (dd, J=8.85, 2.14 Hz, 1H) 6.51 (s, 1H)3.72-3.79 (m, 4H) 3.49-3.53 (m, 4H) 3.36-3.44 (m, 1H) 2.72-2.80 (m, 1H)2.60-2.69 (m, 2H) 2.20-2.39 (m, 6H) 1.54-1.62 (m, 4H) 1.39-1.51 (m, 2H).MS: (M+H)⁺=401.

Example 117 Cis-Pyrazine-2-carboxylicacid-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-amide

The product of Example 101A (59 mg, 0.206 mmole) was dissolved inanhydrous dichloromethane (2.0 mL). To the solution was added 2-pyrazinecarboxylic acid (51 mg, 0.412 mmole),1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (79 mg,0.412 mmole) and 1-hydroxybenzotriazole hydrate (28 mg, 0.206 mmole).The mixture was stirred at room temperature overnight then diluted withwater. The pH of the mixture was was adjusted to pH 9 with 1 N NaOH andextracted three times with dichloromethane. The combined organic layerswere concentrated to give the crude product. The crude product waspurified by column chromatography (0.6% ammonium hydroxide and 6%methanol in dichloromethane) to provide the title compound. ¹H NMR (500MHz, CDCl₃) δ ppm 9.81 (s, 1H) 9.54 (d, J=1.53 Hz, 1H) 8.83 (d, J=2.44Hz, 1H) 8.66 (d, J=2.14 Hz, 1H) 8.58-8.63 (m, 1H) 7.94 (d, J=8.85 Hz,1H) 7.52 (dd, J=8.85, 2.14 Hz, 1H) 3.52-3.62 (m, 1H) 2.74-2.84 (m, 1H)2.61-2.72 (m, 2H) 2.24-2.41 (m, 6H) 1.55-1.64 (m, 4H) 1.40-1.52 (m, 2H).MS: (M+H)⁺=394.

Example 118Cis-N-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-2-thiophen-3-yl-acetamide

The title compound was prepared according to the procedure described inExample 117, except for substituting 3-thiopheneacetic acid for2-pyrazine carboxylic acid. ¹H NMR (500 MHz, CDCl₃) δ ppm 8.34 (d,J=2.14 Hz, 1H) 7.81 (d, J=8.54 Hz, 1H) 7.42 (dd, J=4.88, 3.05 Hz, 1H)7.26-7.32 (m, 1H) 7.13 (dd, J=8.70, 2.29 Hz, 1H) 7.10 (d, J=4.88 Hz, 1H)3.81 (s, 2H) 3.47-3.57 (m, 1H) 2.73-2.81 (m, 1H) 2.61-2.69 (m, 2H)2.23-2.40 (m, 6H) 1.54-1.63 (m, 4H) 1.40-1.50 (m, 2H). MS: (M+H)⁺=412.

Example 119Cis-N-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-3-thiophen-2-yl-propionamide

The title compound was prepared according to the procedure described inExample 117, except for substituting 3-(2-thienyl)propanoic acid for2-pyrazine carboxylic acid. ¹H NMR (500 MHz, CDCl₃) δ ppm 8.37 (d,J=1.83 Hz, 1H) 7.83 (d, J=8.54 Hz, 1H) 7.23 (s, 1H) 7.11-7.19 (m, 2H)6.93 (dd, J=5.03, 3.51 Hz, 1H) 6.88 (d, J=2.75 Hz, 1H) 3.47-3.59 (m, 1H)3.30 (t, J=7.32 Hz, 2H) 2.71-2.82 (m, 3H) 2.60-2.70 (m, 2H) 2.22-2.40(m, 6H) 1.54-1.65 (m, 4H) 1.40-1.50 (m, 2H). MS: (M+H)⁺=426.

Example 120Cis-3-Furan-2-yl-N-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-propionamide

The title compound was prepared according to the procedure described inExample 117, except for substituting 3-(2-furyl)propanoic acid for2-pyrazine carboxylic acid. ¹H NMR (500 MHz, CDCl₃) δ ppm 8.38 (d,J=1.53 Hz, 1H) 7.83 (d, J=8.54 Hz, 1H) 7.34 (s, 1H) 7.25-7.30 (m, 1H)7.16 (dd, J=8.54, 2.14 Hz, 1H) 6.27-6.34 (m, 1H) 6.09 (d, J=2.75 Hz, 1H)3.47-3.59 (m, 1H) 3.10 (t, J=7.32 Hz, 2H) 2.70-2.83 (m, 3H) 2.60-2.69(m, 2H) 2.22-2.40 (m, 6H) 1.54-1.65 (m, 4H) 1.40-1.51 (m, 2H). MS:(M+H)⁺=410.

Example 121 Cis-Pyrimidine-5-carboxylicacid-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-amide

The title compound was prepared according to the procedure described inExample 117, except for substituting 5-pyrimidinecarboxylic acid for2-pyrazine carboxylic acid. ¹H NMR (500 MHz, CDCl₃) δ ppm 9.39 (s, 1H)9.25 (s, 2H) 8.49 (s, 1H) 7.99-8.07 (m, 1H) 7.93 (d, J=8.85 Hz, 1H) 7.41(dd, J=8.85, 2.14 Hz, 1H) 3.52-3.63 (m, 1H) 2.73-2.84 (m, 1H) 2.63-2.73(m, 2H) 2.22-2.42 (m, 6H) 1.54-1.64 (m, 4H) 1.41-1.51 (m, 2H). MS:(M+H)⁺=394.

Example 122Trans-4-Cyano-N-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-benzamide

The title compound was prepared according to the procedure described inExample 101C, except for substituting Example 101B for Example 101A andsubstituting 4-cyanobenzoyl chloride for acetyl chloride. ¹H NMR (400MHz, CDCl₃) δ ppm 8.51 (s, 1H) 8.00 (d, J=8.59 Hz, 2H) 7.91-7.98 (m, 2H)7.78-7.84 (m, 2H) 7.40 (dd, J=8.90, 2.15 Hz, 1H) 3.76-3.88 (m, 1H)3.05-3.16 (m, 1H) 2.49-2.61 (m, 4H) 2.23-2.37 (m, 4H) 1.54-1.66 (m, 4H)1.40-1.53 (m, 2H). MS: (M+H)⁺=417.

Example 123Trans-N-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-Propionamide

The title compound was prepared according to the procedure described inExample 101C, except for substituting Example 101B for Example 101A andsubstituting propionyl chloride for acetyl chloride. ¹H NMR (500 MHz,CDCl₃) δ ppm 8.44 (d, J=1.53 Hz, 1H) 7.87 (d, J=8.85 Hz, 1H) 7.21-7.33(m, 2H) 3.74-3.85 (m, 1H) 3.03-3.16 (m, 1H) 2.49-2.62 (m, 4H) 2.44 (q,J=7.63 Hz, 2H) 2.21-2.38 (m, 4H) 1.56-1.63 (m, 4H) 1.41-1.52 (m, 2H)1.28 (t, J=7.63 Hz, 3H). MS: (M+H)⁺=344.

Example 124Trans-N-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-isobutyramide

The title compound was prepared according to the procedure described inExample 101C, except for substituting Example 101B for Example 101A andsubstituting isobutyryl chloride for acetyl chloride. ¹H NMR (500 MHz,CDCl₃) δ ppm 8.46 (d, J=1.83 Hz, 1H) 7.87 (d, J=8.85 Hz, 1H) 7.29 (s,1H) 7.24-7.26 (m, 1H) 3.77-3.85 (m, 1H) 3.04-3.14 (m, 1H) 2.49-2.61 (m,5H) 2.22-2.37 (m, 4H) 1.56-1.64 (m, 4H) 1.42-1.52 (m, 2H) 1.29 (d,J=6.71 Hz, 6H). MS: (M+H)⁺=358.

Example 125Trans-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-carbamic acidisobutyl ester

The title compound was prepared according to the procedure described inExample 101C, except for substituting Example 101B for Example 101A andsubstituting isobutylchloroformate for acetyl chloride. ¹H NMR (500 MHz,CDCl₃) δ ppm 8.18 (s, 1H) 7.87 (d, J=8.54 Hz, 1H) 7.21 (dd, J=8.85, 2.14Hz, 1H) 6.73 (s, 1H) 3.98 (d, J=6.41 Hz, 2H) 3.74-3.84 (m, 1H) 3.04-3.13(m, 1H) 2.48-2.60 (m, 4H) 2.19-2.38 (m, 4H) 1.95-2.07 (m, 1H) 1.55-1.68(m, 4H) 1.42-1.51 (m, 2H) 0.98 (d, J=6.71 Hz, 6H). MS: (M+H)⁺=388.

Example 126 Trans-Cyclopropanecarboxylicacid[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-amide

The title compound was prepared according to the procedure described inExample 101C, except for substituting Example 101B for Example 101A andsubstituting cyclopropane carbonyl chloride for acetyl chloride. ¹H NMR(500 MHz, CDCl₃) δ ppm 8.42 (s, 1H) 7.87 (d, J=8.85 Hz, 1H) 7.52 (s, 1H)7.22-7.30 (m, 1H) 3.74-3.85 (m, 1H) 3.03-3.15 (m, 1H) 2.49-2.61 (m, 4H)2.19-2.39 (m, 4H) 1.57-1.64 (m, 4H) 1.50-1.57 (m, 1H) 1.41-1.48 (m, 2H)1.08-1.15 (m, 2H) 0.82-0.94 (m, 2H). MS: (M+H)⁺=356.

Example 127 Trans-Cyclobutanecarboxylicacid[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-amide

The title compound was prepared according to the procedure described inExample 101C, except for substituting Example 101B for Example 101A andsubstituting cyclobutane carbonyl chloride for acetyl chloride. ¹H NMR(500 MHz, CDCl₃) δ ppm 8.46 (d, J=1.83 Hz, 1H) 7.87 (d, J=8.85 Hz, 1H)7.24 (dd, J=8.85, 2.14 Hz, 1H) 7.16 (s, 1H) 3.75-3.84 (m, 1H) 3.14-3.23(m, 1H) 3.04-3.14 (m, 1H) 2.50-2.61 (m, 4H) 2.37-2.47 (m, 2H) 2.21-2.37(m, 6H) 1.91-2.08 (m, 2H) 1.56-1.64 (m, 4H) 1.42-1.51 (m, 2H). MS:(M+H)⁺=370.

Example 128 Trans-Cyclopentanecarboxylicacid[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-amide

The title compound was prepared according to the procedure described inExample 101C, except for substituting Example 101B for Example 101A andsubstituting cyclopentane carbonyl chloride for acetyl chloride. ¹H NMR(500 MHz, CDCl₃) δ ppm 8.46 (d, J=1.83 Hz, 1H) 7.87 (d, J=8.85 Hz, 1H)7.31 (s, 1H) 7.24 (dd, J=8.85, 2.14 Hz, 1H) 3.74-3.84 (m, 1H) 3.03-3.13(m, 1H) 2.67-2.76 (m, 1H) 2.51-2.61 (m, 4H) 2.23-2.39 (m, 4H) 1.88-2.01(m, 4H) 1.76-1.86 (m, 2H) 1.56-1.65 (m, 6H) 1.42-1.51 (m, 2H). MS:(M+H)⁺=384.

Example 129 Trans-Cyclohexanecarboxylicacid[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-amide

The title compound was prepared according to the procedure described inExample 101C, except for substituting Example 101B for Example 101A andsubstituting cyclohexane carbonyl chloride for acetyl chloride. ¹H NMR(500 MHz, CDCl₃) δ ppm 8.46 (d, J=1.83 Hz, 1H) 7.87 (d, J=8.85 Hz, 1H)7.24 (dd, J=8.85, 2.14 Hz, 1H) 3.75-3.83 (m, 1H) 3.05-3.14 (m, 1H)2.50-2.60 (m, 4H) 2.21-2.37 (m, 4H) 1.96-2.02 (m, 2H) 1.82-1.90 (m, 2H)1.69-1.76 (m, 1H) 1.54-1.64 (m, 6H) 1.43-1.51 (m, 2H) 1.24-1.40 (m, 4H).MS: (M+H)⁺=398.

Example 130 Trans-Furan-2-carboxylicacid[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-amide

The title compound was prepared according to the procedure described inExample 101C, except for substituting Example 101B for Example 101A andsubstituting 2-furoyl chloride for acetyl chloride. ¹H NMR (500 MHz,CDCl₃) δ ppm 8.54 (d, J=2.14 Hz, 1H) 8.20 (s, 1H) 7.93 (d, J=8.85 Hz,1H) 7.54 (s, 1H) 7.41 (dd, J=8.54, 2.14 Hz, 1H) 7.23-7.31 (m, 1H) 6.59(dd, J=3.51, 1.68 Hz, 1H) 3.76-3.87 (m, 1H) 3.05-3.18 (m, 1H) 2.51-2.64(m, 4H) 2.21-2.41 (m, 4H) 1.54-1.72 (m, 4H) 1.40-1.52 (m, 2H). MS:(M+H)⁺=382.

Example 131 Trans-Morpholine-4-carboxylicacid-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-amide

The title compound was prepared according to the procedure described inExample 101C, except for substituting Example 101B for Example 101A andsubstituting 4-morpholine carbonyl chloride for acetyl chloride. ¹H NMR(400 MHz, CDCl₃) δ ppm 8.16 (s, 1H) 7.84 (s, 1H) 7.84 (s, 1H) 7.18 (d,J=8.59 Hz, 1H) 6.45 (s, 1H) 3.71-3.85 (m, 4H) 3.45-3.56 (m, 4H)3.35-3.45 (m, 1H) 3.04-3.12 (m, 1H) 2.47-2.59 (m, 4H) 2.21-2.38 (m, 4H)1.40-1.67 (m, 4H) 1.20-1.31 (m, 2H). MS: (M+H)⁺=401.

Example 132 Trans-Pyrimidine-5-carboxylicacid-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-amide

The title compound was prepared according to the procedure described inExample 117, except for substituting Example 101B for Example 101A, andsubstituting 5-pyrimidine carboxylic acid for 2-pyrazine carboxylicacid. ¹H NMR (500 MHz, CDCl₃) δ ppm 9.39 (s, 1H) 9.25 (s, 2H) 8.50 (s,1H) 8.05 (s, 1H) 7.96 (d, J=8.85 Hz, 1H) 7.43 (dd, J=8.85, 2.14 Hz, 1H)3.77-3.88 (m, 1H) 3.05-3.16 (m, 1H) 2.57 (t, J=7.17 Hz, 4H) 2.19-2.42(m, 4H) 1.55-1.65 (m, 4H) 1.39-1.54 (m, 2H). MS: (M+H)⁺=394.

Example 133 Trans-Pyrazine-2-carboxylicacid-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-amide

The title compound was prepared according to the procedure described inExample 117, except for substituting Example 101B for Example 101A. ¹HNMR (500 MHz, CDCl₃) δ ppm 9.82 (s, 1H) 9.54 (d, J=1.53 Hz, 1H) 8.84 (d,J=2.44 Hz, 1H) 8.66 (d, J=1.83 Hz, 1H) 8.59-8.64 (m, 1H) 7.97 (d, J=8.54Hz, 1H) 7.54 (dd, J=8.85, 2.14 Hz, 1H) 3.77-3.88 (m, 1H) 3.05-3.18 (m,1H) 2.51-2.62 (m, 4H) 2.19-2.41 (m, 4H) 1.55-1.66 (m, 4H) 1.41-1.52 (m,2H). MS: (M+H)⁺=394.

Example 134Racemic-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-pyrimidin-5-yl-amine

The product of Example 101A(cis-2-(3-piperidin-1-yl-cyclobutyl)-benzothiazole-6-ylamine) (50 mg,0.174 mmole), 5-bromopyrimidine (42 mg, 0.264 mmole),tris(dibenzylideneacetone)dipalladium (0) (6.5 mg, 0.007 mmole),racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP, 8.7 mg,0.014 mmole) and sodium tert-butoxide (23 mg, 0.242 mmole) were chargedin a tube and sealed. The tube was placed on high vacuum for 2 hours andrefilled with nitrogen. Toluene (2 mL) was added and the reaction vesselwas placed in a microwave reactor and heated at 145° C. for 15 minutes.After cooling to room temperature, the mixture was diluted with waterand extracted three times with with dichloromethane. The combinedorganic layers were concentrated and the crude product was purified bycolumn chromatography (0.4% ammonium hydroxide and 4% methanol indichloromethane). The product collected was a mixture of cis and transisomers. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.79 (s, 1H) 8.50-8.56 (m, 2H)7.89 (d, J=8.90 Hz, 1H) 7.58 (d, J=2.15 Hz, 1H) 7.18 (dd, J=8.59, 2.15Hz, 1H) 5.83 (s, 1H) 3.48-3.63 (m, 1H) 2.73-2.85 (m, 1H) 2.59-2.71 (m,2H) 2.23-2.39 (m, 6H) 1.54-1.66 (m, 4H) 1.41-1.51 (m, 2H). MS:(M+H)⁺=366.

Example 135Racemic-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-pyrimidin-2-yl-amine

The product of Example 44A(trans-6-bromo-2-(3-piperidin-1-ylcyclobutyl)-1,3-benzothiazole) (100mg, 0.285 mmole), 2-aminopyrimidine (35 mg, 0.368 mmole),tris(dibenzylideneacetone)dipalladium (0) (10.4 mg, 0.011 mmole),racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP, 14 mg, 0.022mmole) and sodium tert-butoxide (38 mg, 0.400 mmole) were charged in atube and sealed. The tube was placed on high vacuum for 2 hours andrefilled with nitrogen. Toluene (2 mL) was added and the reaction vesselwas placed in a microwave reactor and heated at 145° C. for 15 minutes.After cooling to room temperature, the mixture was diluted with waterand extracted three times with dichloromethane. The combined organiclayers were concentrated under reduced pressure and the crude productwas purified by column chromatography (0.4% ammonium hydroxide and 4%methanol in dichloromethane). The product collected was a mixture of cisand trans isomers (98 mg). ¹H NMR (400 MHz, CDCl₃) δ ppm 8.42-8.49 (m,3H) 7.89 (d, 2H) 7.37-7.46 (m, 2H) 6.75 (t, J=4.76 Hz, 1H) 3.75-3.86 (m,0.6H) 3.48-3.62 (m, 0.4H) 3.03-3.17 (m, 0.6H) 2.73-2.84 (m, 0.4H)2.48-2.72 (m, 4H) 2.21-2.42 (m, 4H) 1.55-1.66 (m, 4H) 1.41-1.51 (m, 2H).MS: (M+H)⁺=366.

Example 136Racemic-(5-bromo-pyrimidin-2-yl)-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-amine

The title compound was prepared according to the procedure described inExample 135, except for substituting 2-amino-5-bromopyrimidine for2-aminopyrimidine. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.45 (s, 2H) 8.39 (dd,J=5.83, 2.15 Hz, 1H) 7.89 (dd, J=11.81, 8.75 Hz, 1H) 7.33-7.43 (m, 2H)7.21-7.26 (m, 1H) 3.76-3.85 (m, 0.4H) 3.49-3.61 (m, 0.6H) 3.04-3.16 (m,0.4H) 2.72-2.85 (m, 0.6H) 2.50-2.71 (m, 4H) 2.22-2.41 (m, 4H) 1.54-1.67(m, 4H) 1.41-1.50 (m, 2H).

Example 137Racemic-(5-methyl-pyridin-2-yl)-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-amine

The title compound was prepared according to the procedure described inExample 135, except for substituting 2-amino-5-methylpyridine for2-aminopyrimidine. ¹H NMR (300 MHz, CDCl₃) δ ppm 8.06 (s, 1H) 7.98 (d,J=2.37 Hz, 1H) 7.85 (d, J=8.82 Hz, 1H) 7.35 (dd, J=8.31, 2.20 Hz, 1H)7.22-7.28 (m, 1H) 6.79 (d, J=8.48 Hz, 1H) 6.46 (s, 1H) 3.76-3.89 (m,0.3H) 3.48-3.61 (m, 0.7H) 3.06-3.22 (m, 0.3H) 2.74-2.87 (m, 0.7H)2.53-2.72 (m, 4H) 2.28-2.44 (m, 4H) 2.25 (s, 3H) 1.53-1.71 (m, 4H)1.39-1.52 (m, 2H). MS: (M+H)⁺=379.

Example 138Racemic-6-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-ylamino]-nicotinonitrile

The title compound was prepared according to the procedure described inExample 135, except for substituting 2-amino-5-cyanopyridine for2-aminopyrimidine. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.49 (t, J=2.45 Hz, 1H)7.90-8.04 (m, 2H) 7.67 (dd, J=8.75, 2.30 Hz, 1H) 7.30-7.39 (m, 1H) 6.99(s, 1H) 6.77 (dd, J=8.44, 2.92 Hz, 1H) 3.75-3.87 (m, 0.3H) 3.50-3.66 (m,0.7H) 3.04-3.17 (m, 0.3H) 2.75-2.85 (m, 0.7H) 2.51-2.73 (m, 4H)2.22-2.40 (m, 4H) 1.61 (s, 4H) 1.40-1.51 (m, 2H). MS: (M+H)⁺=390.

Example 1392-{Trans-3-[(S)-2-methylpiperidin-1-yl]cyclobutyl}-1,3-benzothiazol-6-yl-azetidin-2-oneExample 139A6-Bromo-2-{trans-3-[(S)-2-methylpiperidin-1-yl]cyclobutyl}-1,3-benzothiazole

The title compound was prepared according to the procedure described inExample 1E, substituting (S)-2-methylpiperidine for2-(R)-methylpyrrolidine. ¹H NMR (300 MHz, CDCl₃): δ=7.98 ppm (d, J=2.3Hz, 1H), 7.83 (d, J=8.5 Hz, 1H), 7.56 (dd, J=8.5, 2.3 Hz, 1H), 3.75 (m,1H), 3.53 (m, 1H), 2.50-2.85 (m, 6H), 2.19 (m, 1H), 1.65 (m, 4H), 1.41(m, 2H), 1.06 (d, J=6.8 Hz, 3H). MS (ESI, M+H⁺): 365.9.

Example 139B2-{Trans-3-[(S)-2-methylpiperidin-1-yl]cyclobutyl}-1,3-benzothiazol-6-yl-azetidin-2-one

To a microwave vial equipped with magnetic stir bar, Example 139A (50mg, 0.14 mmol) was added, followed by azetidin-2-one (50 mg, 0.7 mmol),Pd₂(dba)₃ (3.5 mg, 0.004 mmol), Xantphos (6.1 mg, 0.011 mmol, StremChemicals, 7 Mulliken Way, Newburyport, Mass. 01950-4098) and CsCO₃ (65mg, 0.2 mmol). The reaction vial was then sealed with an aluminum cap,and purged with N₂ for at least 10 times. Dioxane (2 mL) was thenintroduced via a syringe. The mixture was then sonicated, and thenheated in a microwave oven at 200° C. for 20 minutes. The mixture wascooled down to 23° C., and filtered. Solvent was removed under reducedpressure, the residue purified via chromatography (SiO₂, ethyl acetate(0-80%)/hexanes) to give the titled compound. ¹H NMR (300 MHz, CDCl₃):δ=7.97 ppm (d, J=2.0 Hz, 1H), 7.92 (d, J=8.5 Hz, 1H), 7.38 (dd, J=8.5,2.0 Hz, 1H), 3.75 (m, 1H), 3.71 (t, J=4.7 Hz, 2H), 3.46 (m, 1H), 3.17(t, J=4.7 Hz, 2H), 2.64 (m, 3H), 2.51 (m, 3H), 2.11 (m, 1H), 1.64 (m,4H), 1.38 (m, 2H), 1.01 (d, J=6.5 Hz, 3H). MS (ESI, M+H⁺): 356.1.

Example 1402-{Trans-3-[(S)-2-methylpiperidin-1-yl]cyclobutyl}-1,3-benzothiazol-6-yl-pyrrolidin-2-one

The title compound was prepared according to the procedure described inExample 139B, substituting pyrrolidin-2-one for azetidin-2-one. ¹H NMR(300 MHz, CDCl₃): δ=8.29 ppm (d, J=2.3 Hz, 1H), 7.95 (d, J=9.1 Hz, 1H),7.58 (dd, J=9.1, 2.3 Hz, 1H), 3.94 (t, J=4.8 Hz, 2H), 3.74 (m, 1H), 3.47(m, 1H), 2.48-2.73 (m, 8H), 2.21 (m, 2H), 2.11 (m, 1H), 1.62 (m, 4H),1.38 (m, 1H), 1.02 (d, J=6.5 Hz, 3H). MS (ESI, M+H⁺): 370.1.

Example 1412-{Trans-3-[(S)-2-methylpiperidin-1-yl]cyclobutyl}-1,3-benzothiazol-6-yl-piperidin-2-one

The title compound was prepared according to the procedure described inExample 139B, substituting piperidin-2-one for azetidin-2-one. ¹H NMR(300 MHz, CDCl₃): δ=7.98 ppm (d, J=8.5 Hz, 1H), 7.75 (d, J=2.0 Hz, 1H),7.33 (dd, J=8.5, 2.0 Hz, 1H), 3.75 (m, 1H), 3.70 (t, J=6.1 Hz, 2H), 3.52(m, 1H), 2.49-2.80 (m, 8H), 2.14 (m, 1H), 1.97 (m, 4H), 1.60 (m, 4H),1.43 (m, 2H), 1.06 (m, 3H). MS (ESI, M+H⁺): 384.1.

Example 1422-{Trans-3-[(S)-2-methylpiperidin-1-yl]cyclobutyl}-1,3-benzothiazol-6-yl-homopyrrolidin-2-one

The title compound was prepared according to the procedure described inExample 139B, substituting homopyrrolidin-2-one for azetidin-2-one. ¹HNMR (300 MHz, CDCl₃): δ=7.96 ppm (d, J=8.4 Hz, 1H), 7.71 (d, J=2.7 Hz,1H), 7.29 (dd, J=8.4, 2.7 Hz, 1H), 3.80 (m, 2H), 3.76 (m, 1H), 3.49 (m,1H), 3.73 (m, 2H), 2.66 (m, 4H), 2.50 (m, 2H), 2.10 (m, 1H), 1.86 (m,6H), 1.62 (m, 4H), 1.41 (m, 1H), 1.04 (m, 3H). MS (ESI, M+H⁺): 398.2.

Example 1432-{Trans-3-[(S)-2-methylpiperidin-1-yl]cyclobutyl}-1,3-benzothiazole-6-carboxamideExample 143A Methyl2-{trans-3-[(S)-2-methylpiperidin-1-yl]cyclobutyl}-1,3-benzothiazole-6-carboxylate

6-bromo-2-{trans-3-[(S)-2-methylpiperidin-1-yl]cyclobutyl}-1,3-benzothiazole(Example 139A, 2.0 g, 5.5 mmol) was dissolved in methanol (60 mL),followed by catalyst PdCl₂(dppf)CH₂Cl₂ (225 mg, 0.3 mmol, also known asPalladium(II) chloride-1,1′-bis(diphenylphosphino)ferrocene, CAS#72287-264), and heated at 80° C. under CO pressure (60 psi) for 2hours. The mixture was then cooled down to 23° C., and filtrated.Solvent was removed under reduced pressure and the residue was purifiedvia chromatography (SiO₂, 10-80% ethyl acetate in hexanes) to give thetitled compound. ¹H NMR (300 MHz, CDCl₃): δ=8.58 ppm (d, J=1.7 Hz, 1H),8.16 (dd, J=8.5, 1.7 Hz, 1H), 8.01 (d, J=8.5 Hz, 1H), 4.10 (m, 2H), 4.00(m, 1H), 3.97 (s, 3H), 3.72 (m, 1H), 3.52 (m, 1H), 3.49 (d, J=4.1 Hz,3H), 2.76 (m, 4H), 1.60 (m, 2H), 1.40 (m, 2H), 1.00 (m, 2H). MS (ESI,M+H⁺): 345.1.

Example 143B2-{Trans-3-[(S)-2-methylpiperidin-1-yl]cyclobutyl}-1,3-benzothiazole-6-carboxylicacid

Methyl2-{trans-3-[(S)-2-methylpiperidin-1-yl]cyclobutyl}-1,3-benzothiazole-6-carboxylate(Example 143A, 2.0 g, 5.8 mmol) was dissolved in methanol (600 mL),followed by H₂O (300 mg, 16.7 mmol) and sodium methoxide (1.4 g, 26mmol) at 23° C. The reaction mixture was then allowed to stir at 23° C.for 1 day. Solvent and excess of water were removed. HCl (2N) was addedto make the mixture slightly acidic (pH ˜5-6). Excess of water wasremoved. The solid was triturated with CH₂Cl₂/MeOH, and filtrated. Thesolvents of the filtrate were removed under vacuum. The residue wastreated with CH₂Cl₂ and filtrated again. Removal of the solvent gave thedesired product as an off-white solid (2.13 g, 100%). ¹H NMR (300 MHz,CD₃OD): δ=8.54 ppm (d, J=1.3 Hz, 1H), 8.11 (dd, J=8.9, 1.3 Hz, 1H), 7.91(d, J=8.9 Hz, 1H), 4.00 (m, 1H), 3.80 (m, 1H), 2.70-3.10 (m, 7H), 2.00(m, 2H), 1.80 (m, 2H), 1.65 (m, 2H), 1.41 (d, J=6.8 Hz, 3H). MS (ESI,M+H⁺): 331.0.

Example 143C2-{Trans-3-[(S)-2-methylpiperidin-1-yl]cyclobutyl}-1,3-benzothiazole-6-carboxamide

2-{trans-3-[(S)-2-methylpiperidin-1-yl]cyclobutyl}-1,3-benzothiazole-6-carboxylicacid (Example 143B, 20 mg, 0.062 mmol) was added to a solution of oxalylchloride (17 mg, 0.13 mmol) in CH₂Cl₂ (1 mL) at 23° C., followed by 1drop of catalytic amount of DMF. The reaction mixture was allowed tostir for 1 h. Solvent and excess of oxalyl chloride were removed undervacuum, the residue solid was re-dissolved in CH₂Cl₂ (0.5 mL). Excess ofammonia (2 mL, 1.2 mmol) in CH₂Cl₂ (2 mL) was then added to the reactionvial. The reaction mixture was then stirred overnight. Solvent wasremoved, and the crude product was purified via HPLC (C-18 column, 0.1%TFA in acetonitrile) to give 16 mg product as a TFA salt (65%). ¹H NMR(500 MHz, CD₃OD): δ=8.51 ppm (m, 1H), 8.01 (m, 2H), 4.00 (m, 1H), 3.80(m, 1H), 3.83 (m, 2H), 2.80-3.15 (m, 5H), 2.74 (m, 1H), 1.94 (m, 3H),1.75 (m, 3H), 1.41 (m, 3H). MS (ESI, M+H⁺): 330.0.

Example 144N-Isopropyl-2-{trans-3-[(S)-2-methylpiperidin-1-yl]cyclobutyl}-1,3-benzothiazole-6-carboxamide

The title compound was prepared according to the procedure described inExample 143C, substituting 2-isopropylamine for ammonia. ¹H NMR (300MHz, CD₃OD): δ=8.43 ppm (m, 1H), 7.94-8.03 (m, 2H), 4.23 (m, 1H), 3.96(m, 2H), 3.02 (m, 1H), 2.93 (m, 3H), 2.86 (m, 2H), 1.94 (m, 3H), 1.75(m, 3H), 1.40 (m, 3H), 1.30 (d, J=6.7 Hz, 6H). MS (ESI, M+H⁺): 372.1.

Example 145 N-cyclopropyl-2-{trans-3-[(S)-2-methylpiperidin-1-yl]cyclobutyl}-1,3-benzothiazole-6-carboxamide

The title compound was prepared according to the procedure described inExample 143C, substituting cyclopropylamine for ammonia. ¹H NMR (300.MHz, CD₃OD): δ=8.43 ppm (m, 1H), 7.93-8.02 (m, 2H), 4.00 (m, 1H), 3.82(m, 2H), 3.02 (m, 1H), 2.90 (m, 4H), 2.86 (m, 2H), 1.94 (m, 3H), 1.69(m, 3H), 1.40 (m, 3H), 0.82 (m, 2H), 0.67 (m, 2H). MS (ESI, M+H⁺):370.1.

Example 146N-phenyl-2-{trans-3-[(S)-2-methylpiperidin-1-yl]cyclobutyl}-1,3-benzothiazole-6-carboxamide

The title compound was prepared according to the procedure described inExample 143C, substituting aniline for ammonia. ¹H NMR (300 MHz, CD₃OD):δ=8.57 ppm (m, 1H), 8.04-8.10 (m, 2H), 7.71 (d, J=7.6 Hz, 2H), 7.37 (m,2H), 7.16 (t, J=7.7 Hz, 1H), 4.00 (m, 1H), 3.82 (m, 2H), 3.07 (m, 1H),2.96 (m, 3H), 2.87 (m, 2H), 1.94 (m, 3H), 1.75 (m, 3H), 1.41 (m, 3H). MS(ESI, M+H⁺): 406.1.

Example 147N-thiazol-2-yl-2-{trans-3-[(S)-2-methylpiperidin-1-yl]cyclobutyl}-1,3-benzothiazole-6-carboxamide

The title compound was prepared according to the procedure described inExample 143C, substituting 2-aminothiazole for ammonia. ¹H NMR (300 MHz,CD₃OD): δ=8.68 ppm (m, 1H), 8.17 (m, 1H), 8.09 (m, 1H), 7.53 (d, J=3.6Hz, 1H), 7.19 (d, J=3.6 Hz, 1H), 4.00 (m, 1H), 3.85 (m, 2H), 3.10 (m,1H), 2.95 (m, 3H), 2.76 (m, 2H), 1.94 (m, 3H), 1.73 (m, 3H), 1.41 (m,3H). MS (ESI, M+H⁺): 413.1.

Example 148N-benzyl-2-{trans-3-[(S)-2-methylpiperidin-1-yl]cyclobutyl}-1,3-benzothiazole-6-carboxamide

The title compound was prepared according to the procedure described inExample 143C, substituting 2-benzylamine for ammonia. ¹H NMR (300 MHz,CD₃OD): δ=8.48 ppm (m, 1H), 8.00 (m, 2H), 7.38 (m, 2H), 7.33 (m, 2H),7.25 (m, 1H), 4.61 (s, 2H), 4.00 (m, 1H), 3.82 (m, 2H), 3.04 (m, 1H),2.93 (m, 3H), 2.73 (m, 2H), 1.94 (m, 3H), 1.73 (m, 3H), 1.40 (m, 3H). MS(ESI, M+H⁺): 420.1.

Example 149N-(2-phenethyl)-2-{trans-3-[(S)-2-methylpiperidin-1-yl]cyclobutyl}-1,3-benzothiazole-6-carboxamide

The title compound was prepared according to the procedure described inExample 143C, substituting 2-phenethylamine for ammonia. ¹H NMR (300MHz, CD₃OD): δ=8.40 ppm (m, 1H), 8.00 (m, 1H), 7.91 (m, 1H), 7.27 (m,3H), 7.20 (m, 2H), 4.00 (m, 1H), 3.82 (m, 2H), 3.63 (t, J=7.0 Hz, 2H),3.04 (m, 1H), 2.94 (t, J=7.0 Hz, 2H), 2.83 (m, 3H), 2.75 (m, 2H), 1.94(m, 3H), 1.73 (m, 3H), 1.40 (m, 3H). MS (ESI, M+H⁺): 434.2.

Example 150N,N-dimethyl-2-{trans-3-[(S)-2-methylpiperidin-1-yl]cyclobutyl}-1,3-benzothiazole-6-carboxamide

The title compound was prepared according to the procedure described inExample 143C, substituting dimethylamine for ammonia. ¹H NMR (300 MHz,CD₃OD): δ=8.08 ppm (m, 1H), 8.03 (m, 1H), 7.58 (m, 1H), 4.00 (m, 1H),3.83 (m, 2H), 3.14 (s, 3H), 3.08 (m, 1H), 3.03 (s, 3H), 2.90 (m, 3H),2.72 (m, 2H), 1.92 (m, 3H), 1.68 (m, 3H), 1.40 (m, 3H). MS (ESI, M+H⁺):358.1.

Example 151(Pyrrolidin-1-yl)-2-{trans-3-[(S)-2-methylpiperidin-1-yl]cyclobutyl}-1,3-benzothiazole-6-methanone

The title compound was prepared according to the procedure described inExample 143C, substituting pyrrolidine for ammonia. ¹H NMR (300 MHz,CD₃OD): δ=8.17 ppm (m, 1H), 8.03 (m, 1H), 7.68 (m, 1H), 4.00 (m, 1H),3.81 (m, 2H), 3.63 (t, J=6.7 Hz, 2H), 3.49 (t, J=6.7 Hz, 2H), 3.08 (m,1H), 2.90 (m, 3H), 2.75 (m, 2H), 1.92 (m, 7H), 1.68 (m, 3H), 1.40 (m,3H). MS (ESI, M+H⁺): 384.1.

Example 1522-[Trans-3-(piperidin-1-yl)cyclobutyl]-1,3-benzothiazol-6-yl-3-methyl-pyrrolidin-2-oneExample 152A6-Bromo-2-[trans-3-(piperidin-1-yl)cyclobutyl]-1,3-benzothiazole

The title compound was prepared according to the procedure described inExample 1E, substituting piperidine for 2-(R)-methylpyrrolidine. ¹H NMR(300 MHz, CDCl₃): δ=7.98 ppm (d, J=2.0 Hz, 1H), 7.83 (d, J=8.5 Hz, 1H),7.55 (dd, J=8.5, 2.0 Hz, 1H), 3.80 (m, 1H), 3.09 (m, 1H), 2.56 (m, 4H),2.30 (m, 4H), 1.61 (m, 4H), 1.47 (m, 2H). MS (ESI, M+H⁺): 351.9.

Example 152B2-[Trans-3-(piperidin-1-yl)cyclobutyl]-1,3-benzothiazol-6-yl-3-methyl-pyrrolidin-2-one

To a microwave vial equipped with magnetic stir bar,6-bromo-2-[trans-3-(piperidin-1-yl)cyclobutyl]-1,3-benzothiazole (3, 50mg, 0.14 mmol) was added, Pd₂(dba)₃ (4.0 mg, 0.004 mmol), Xantphos (6.9mg, 0.012 mmol) and CsCO₃ (68 mg, 0.2 mmol), followed by3-methylpyrrolidin-2-one (50 mg, 0.5 mmol). The reaction vial was thensealed with an aluminum cap, and placed under inert atmosphere bypurging with N₂. Dioxane (2 mL) was then introduced via a syringe. Thereaction mixture was then subjected to sonication briefly to ensuremixing of the contents, and then heated in a commercial microwave ovenat 150° C. for 60 min. The reaction mixture was cooled down to 23° C.,and filtered to remove solids. The solvent was removed under vacuum, andfrom this, the residual mixture was purified by chromatography (SiO₂,ethyl acetate (0-80%)/hexanes) to give the title compound as a pureproduct (28 mg, 55%). ¹H NMR (300 MHz, CDCl₃): δ=8.33 ppm (d, J=2.1 Hz,1H), 7.94 (d, J=9.2 Hz, 1H), 7.61 (dd, J=9.2, 2.1 Hz, 1H), 3.85 (m, 3H),2.72 (m, 1H), 2.59 (m, 4H), 2.43 (m, 2H), 2.40 (m, 2H), 1.82 (m, 1H),1.40-1.75 (m, 8H), 1.33 (d, J=7.1 Hz, 3H). MS (ESI, M+H⁺): 370.1.

Example 1532-[Trans-3-(piperidin-1-yl)cyclobutyl]-1,3-benzothiazol-6-yl-oxazolidin-2-one

The title compound was prepared according to the procedure described inExample 152B, substituting oxazolidin-2-one for azetidin-2-one. ¹H NMR(300 MHz, CDCl₃): δ=8.14 ppm (d, J=2.4 Hz, 1H), 7.95 (d, J=9.1 Hz, 1H),7.62 (dd, J=9.1, 2.4 Hz, 1H), 4.55 (m, 2H), 4.15 (m, 2H), 3.97 (m, 1H),3.70 (m, 2H), 3.36 (m, 3H), 2.70 (m, 4H), 1.50-2.00 (m, 6H). MS (ESI,M+H⁺): 358.0.

Example 1542-[Trans-3-(piperidin-1-yl)cyclobutyl]-1,3-benzothiazol-6-yl-3-methylimidazolidin-2-one

The title compound was prepared according to the procedure described inExample 152B, substituting 3-methylimidazolidin-2-one forazetidin-2-one. ¹H NMR (300 MHz, CDCl₃): δ=8.12 ppm (d, J=2.4 Hz, 1H),7.89 (d, J=8.9 Hz, 1H), 7.65 (dd, J=8.9, 2.4 Hz, 1H), 3.88 (m, 3H), 3.75(m, 1H), 3.52 (m, 2H), 3.23 (m, 4H), 2.93 (s, 3H), 2.70 (m, 4H),1.50-2.00 (m, 6H). MS (ESI, M+H⁺): 371.1.

Determination of Biological Activity

To determine the effectiveness of representative compounds of thisinvention as histamine-3 receptor ligands (H₃ receptor ligands), thefollowing tests were conducted according to previously described methods(see European Journal of Pharmacology, 188:219-227 (1990); Journal ofPharmacology and Experimental Therapeutics, 275:598-604 (1995); Journalof Pharmacology and Experimental Therapeutics, 276:1009-1015 (1996); andBiochemical Pharmacology, 22:3099-3108 (1973)).

The rat H₃ receptor was cloned and expressed in cells, and competitionbinding assays carried out, according to methods previously described(see Esbenshade, et al. Journal of Pharmacology and ExperimentalTherapeutics, vol. 313:165-175, 2005; Esbenshade et al., BiochemicalPharmacology 68 (2004) 933-945; Krueger, et al. Journal of Pharmacologyand Experimental Therapeutics, vol. 314:271-281, 2005. Membranes wereprepared from C6 or HEK293 cells, expressing the rat histamine H₃receptor, by homogenization on ice in TE buffer (50 mM Tris-HCl buffer,pH 7.4, containing 5 mM EDTA), 1 mM benzamidine, 2 μg/ml aprotinin, 1μg/ml leupeptin, and 1 μg/ml pepstatin. The homogenate was centrifugedat 40,000 g for 20 minutes at 4° C. This step was repeated, and theresulting pellet was resuspended in TE buffer. Aliquots were frozen at−70° C. until needed. On the day of assay, membranes were thawed anddiluted with TE buffer.

Membrane preparations were incubated with [³H]-N-α-methylhistamine(0.5-1.0 nM) in the presence or absence of increasing concentrations ofligands for H₃ receptor competition binding. The binding incubationswere conducted in a final volume of 0.5 ml TE buffer at 25° C. and wereterminated after 30 minutes. Thioperamide (30 μM) was used to definenon-specific binding. All binding reactions were terminated byfiltration under vacuum onto polyethylenimine (0.3%) presoakedUnifilters (Perkin Elmer Life Sciences) or Whatman GF/B filters followedby three brief washes with 2 ml of ice-cold TE buffer. Bound radiolabelwas determined by liquid scintillation counting. For all of theradioligand competition binding assays, IC₅₀ values and Hill slopes weredetermined by Hill transformation of the data and pK_(i) values weredetermined by the Cheng-Prusoff equation.

Generally, representative compounds of the invention demonstratedbinding affinities in the above assay from about 0.01 nM to about 500nM. Preferred compounds of the invention bound to histamine-3 receptorswith binding affinities from about 0.01 nM to about 10 nM. Morepreferred compounds of the invention bound to histamine-3 receptors withbinding affinities from about 0.01 nM to about 0.9 nM.

Compounds of the invention are histamine-3 receptor ligands thatmodulate function of the histamine-3 receptor by altering the activityof the receptor. These compounds may be inverse agonists that inhibitthe basal activity of the receptor or they may be antagonists thatcompletely block the action of receptor-activating agonists. Thesecompounds may also be partial agonists that partially block or partiallyactivate the histamine-3 receptor or they may be agonists that activatethe receptor.

It is understood that the foregoing detailed description andaccompanying examples are merely illustrative and are not to be taken aslimitations upon the scope of the invention, which is defined solely bythe appended claims and their equivalents. Various changes andmodifications to the disclosed embodiments will be apparent to thoseskilled in the art. Such changes and modifications, including withoutlimitation those relating to the chemical structures, substituents,derivatives, intermediates, syntheses, formulations, or methods, or anycombination of such changes and modifications of use of the invention,may be made without departing from the spirit and scope thereof.

1. A compound of formula:

or a pharmaceutically acceptable salt thereof, wherein: m is 0 or 1; oneof R₁ and R₂ is hydrogen, acyl, acyloxy, alkenyl, alkoxy, alkoxyalkoxy,alkoxyalkyl, alkoxycarbonyl, alkoxyimino, alkoxysulfonyl, alkyl,alkylcarbonyl, alkylsulfonyl, alkynyl, amido, carboxy, cyano,cycloalkyl, fluoroalkoxy, haloalkoxy, haloalkyl, halogen, hydroxy,hydroxyalkyl, mercapto, nitro, alkylthio, —NR_(A)R_(B),(NR_(A)R_(B))carbonyl, —SO₂N(R_(14a))(R_(14b)), —N(R_(14a))SO₂(R_(14b)),a group of the formula —L₂—R₆, or a group of the formula—L_(3a)—R_(6a)—L_(3b)—R_(6b); the other of R₁ and R₂ is selected fromthe group consisting of hydrogen, cyano, halogen, alkyl, cycloalkyl,fluoroalkyl, alkoxy, alkoxyalkyl, fluoroalkoxy, alkylthio,—SO₂N(R_(14a))(R_(14b)), and —N(R_(14a))SO₂(R_(14b)); R_(3a) and R_(3b)are each independently selected from the group consisting of hydrogen,cyano, halogen, alkyl, cycloalkyl, fluoroalkyl, alkoxy, alkoxyalkyl,fluoroalkoxy, alkylthio, —SO₂N(R_(14a))(R_(14b)), and—N(R_(14a))SO₂(R_(14b)); R₄ and R₅ are each independently selected fromthe group consisting of alkyl, fluoroalkyl, hydroxyalkyl, alkoxyalkyl,and cycloalkyl; or R₄ and R₅ taken together with the nitrogen atom towhich each is attached form a non-aromatic ring; R₆ is aryl, heterocycleor heterocyclealkyl; R_(6a) is aryl or heterocycle; R_(6b) is aryl orheterocycle; L is a bond or alkylene; L₂ is a bond, —O—, alkylene,—C(═O)—, —S—, —SO₂N(R_(14a))—, N(R_(14a))SO²⁻—, —C(O)N(R_(14a))—,—N(R_(14a))C(O)—, or —N(R₁₅)—; L_(3a) and L_(3b) are each independentlyselected from the group consisting of a bond, —O—, alkylene, —C(═O)—,—S—, —SO₂N(R_(14a))—, —N(R_(14a))SO²⁻—, —C(O)N(R_(14a))—,N(R_(14a))C(O)—, and —N(R₁₅)—; R₁₀ is selected from the group consistingof hydrogen, cyano, fluoro, hydroxy, and alkyl; R_(14a) and R_(14b) areeach independently selected at each occurrence from the group consistingof hydrogen, alkyl, and cycloalkyl; R₁₅ is selected from the groupconsisting of hydrogen, alkyl, acyl, alkoxycarbonyl, and(R_(14a))(R_(14b))NC(O)—; and R_(A) and R_(B) are independently selectedfrom hydrogen, alkyl, acyl, haloalkyl, alkoxycarbonyl, cycloalkyl, andformyl.
 2. The compound of claim 1, wherein R₁ is —L₂—R₆, wherein L₂ isa bond and R₆ is as defined in claim
 1. 3. The compound of claim 2,wherein R₆ is a heterocycle which may be unsubstituted, or alternativelymay be optionally substituted with one or more substituents chosen fromthe list of acyl, acyloxy, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxyimino, alkoxysulfonyl, alkyl, alkylcarbonyl,alkylsulfonyl, alkynyl, amido, carboxy, cyano, cycloalkyl, fluoroalkoxy,formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto,nitro, oxo, alkylthio, —NR_(A)R_(B), (NR_(A)R_(B))carbonyl,—SO₂N(R_(14a))(R_(14b)), and —N(R_(14a))SO₂(R_(14b)).
 4. The compound ofclaim 3, wherein R₆ is selected from the group consisting of furyl,imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, pyrazinyl, pyrazolyl,pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiadiazolyl,thiadiazolonyl, thiadiazinonyl, oxadiazolyl, oxadiazolonyl,oxadiazinonyl, thiazolyl, thienyl, triazinyl, triazolyl, triazolyl,pyridazinonyl, pyridonyl, pyrimidinonyl, indolyl, benzothienyl,benzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl,benzoisothiazolyl, benzoisoxazolyl, quinolinyl, isoquinolinyl,quinazolinyl, quinoxalinyl, phthalazinyl, pteridinyl, purinyl,naphthyridinyl, cinnolinyl, thieno[2,3-d]imidazole, pyrrolopyrimidinyl,azepanyl, azetidinyl, aziridinyl, azocanyl, morpholinyl, piperazinyl,piperidinyl, pyrrolidinyl, pyrrolinyl, dihydrothiazolyl,dihydropyridinyl, thiomorpholinyl, dioxanyl, dithianyl, tetrahydrofuryl,dihydropyranyl, tetrahydropyranyl, and [1,3]dioxolanyl.
 5. The compoundof claim 4, wherein R₆ is selected from the group consisting ofcyanophenyl, pyrazolyl, pyrimidinyl, pyrimidinonyl, pyridinyl,pyridazinonyl, and quinolinyl, wherein each ring is substituted with 0,1, or 2 substituents selected from methoxy and methyl.
 6. The compoundof claim 1, wherein R_(3a) and R_(3b) are both hydrogen.
 7. The compoundof claim 1, wherein R₄ and R₅ taken together with the nitrogen atom towhich each is attached form a non-aromatic ring, wherein thenon-aromatic ring is a 4- to 9-membered non-aromatic ring.
 8. Thecompound of claim 7, wherein the non-aromatic ring is a ring of thestructure:

Q₁ is O, S, —N(R₂₀)—, or C; Q₂ is —N(R₂₀)— or C; Q₃ is N or C; R₂₀ isselected from the group consisting of hydrogen, alkyl and alkylcarbonyl;p1 and p2 are each independently 1, 2 or 3; q1, q2, q3, q4, and q5 areeach independently 0, 1, or 2; and r1, r2 and r3 are each independently1 or 2; wherein each carbon atom in the ring is substituted withhydrogen, or with 0, 1, or 2 substituents independently selected at eachoccurrence from the group consisting of hydrogen, hydroxy, fluoro,alkyl, hydroxyalkyl, fluoroalkyl, cycloalkyl, cyano, fluoroalkoxy,alkoxyalkyl, alkoxy, fluoroalkoxy, haloalkyl, and N(R_(21a))(R_(21b)),wherein R_(21a) and R_(21b) are each independently selected from thegroup consisting of hydrogen, alkyl, and alkylcarbonyl.
 9. The compoundof claim 1, wherein R₄ and R₅ are taken together with the nitrogen atomto which each is attached to form azepanyl, azetidinyl, aziridinyl,azocanyl, morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl,pyrrolinyl, and hexahydropyrrolo[3,4-b]pyrrolyl, wherein each group issubstituted with 0, 1, or 2 substituents selected from alkyl,hydroxyalkyl, and fluoro.
 10. The compound of claim 1, where m is 0, Lis a bond, and R₆ is heterocycle.
 11. The compound of claim 1, whereinthe compound has the formula (II):

wherein R₁, R₂, R_(3a), R_(3b), R₄, and R₅ are as defined in claim 1.12. The compound of claim 1, wherein the compound has the formula (III):

wherein R₁, R₂, R_(3a), R_(3b), R₄, and R₅ are as defined in claim 1.13. The compound of claim 1, wherein one of R₁ and R₂ is L₂R₆, L₂ is abond, and R₆ is a structure of formula:

wherein R₁₆ and R₁₇ each are independently selected from hydrogen,alkyl, haloalkyl, cycloalkyl, alkoxyalkyl, aryl, and heteroaryl; or R₁₆and R₁₇ taken together with the carbon atom to which each is attachedform a 3- to 7-membered ring; v is 1, 2, 3, 4, 5, or
 6. 14. The compoundof claim 1, selected from the group consisting of:Trans-2-{3-[(2R)-2-methylpyrrolidin-1-yl]cyclobutyl}-6-pyrimidin-5-yl-1,3-benzothiazole;Trans-6-(2,6-dimethylpyridin-3-yl)-2-{3-[(2R)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazole;Trans-6-(2,4-dimethoxypyrimidin-5-yl)-2-{3-[(2R)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazole;Trans-6-(2-methoxypyrimidin-5-yl)-2-{3-[(2R)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazole;Trans-2-{3-[(2R)-2-methylpyrrolidin-1-yl]cyclobutyl}-6-pyridin-4-yl-1,3-benzothiazole;Trans-6-(6-methoxypyridin-3-yl)-2-{3-[(2R)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazole;Trans-2-{3-[(2R)-2-methylpyrrolidin-1-yl]cyclobutyl}-6-pyridin-3-yl-1,3-benzothiazole;Trans-3-(2-{3-[(2R)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazol-6-yl)quinoline;Trans-6-(6-fluoropyridin-3-yl)-2-{3-[(2R)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazole;Trans-4-(2-{3-[(2R)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazol-6-yl)benzonitrile;Trans-2-{3-[(2S)-2-methylpyrrolidin-1-yl]cyclobutyl}-6-pyrimidin-5-yl-1,3-benzothiazole;Trans-6-(2,4-dimethoxypyrimidin-5-yl)-2-{3-[(2S)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazole;Trans-6-(2,6-dimethylpyridin-3-yl)-2-{3-[(2S)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazole;Trans-6-(2-methoxypyrimidin-5-yl)-2-{3-[(2S)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazole;Trans-6-(6-methoxypyridin-3-yl)-2-{3-[(2S)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazole;Trans-3-(2-{3-[(2S)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazol-6-yl)quinoline;Cis-2-{3-[(2R)-2-methylpyrrolidin-1-yl]cyclobutyl}-6-pyrimidin-5-yl-1,3-benzothiazole;Cis-6-(2,6-dimethylpyridin-3-yl)-2-{3-[(2R)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazole;Cis-2-{3-[(2S)-2-methylpyrrolidin-1-yl]cyclobutyl}-6-pyrimidin-5-yl-1,3-benzothiazole;Cis-6-(2,4-dimethoxypyrimidin-5-yl)-2-{3-[(2S)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazole;Cis-6-(2,6-dimethylpyridin-3-yl)-2-{3-[(2S)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazole;Trans-2-(2-{3-[(2R)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazol-6-yl)pyridazin-3(2H)-one;Trans-6-methyl-2-(2-{3-[(2R)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazol-6-yl)pyridazin-3(2H)-one;Trans-5-methyl-1-(2-{3-[(2R)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazol-6-yl)pyridin-2(1H)-one;Trans-3-methyl-1-(2-{3-[(2R)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazol-6-yl)pyridin-2(1H)-one;Trans-2-(2-{3-[(2S)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazol-6-yl)pyridazin-3(2H)-one;Trans-6-methyl-2-(2-{3-[(2S)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazol-6-yl)pyridazin-3(2H)-one;Trans-5-methyl-1-(2-{3-[(2S)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazol-6-yl)pyridin-2(1H)-one;Trans-3-methyl-1-(2-{3-[(2S)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazol-6-yl)pyridin-2(1H)-one;Cis-6-pyrimidin-5-yl-2-(3-pyrrolidin-1-ylcyclobutyl)-1,3-benzothiazole;Cis-6-(2-methoxypyrimidin-5-yl)-2-(3-pyrrolidin-1-ylcyclobutyl)-1,3-benzothiazole;Cis-2-(3-piperidin-1-ylcyclobutyl)-6-pyrimidin-5-yl-1,3-benzothiazoleCis-6-(2-methoxypyrimidin-5-yl)-2-(3-piperidin-1-ylcyclobutyl)-1,3-benzothiazole;Cis-2-(3-azepan-1-ylcyclobutyl)-6-pyrimidin-5-yl-1,3-benzothiazole;Cis-2-(3-morpholin-4-ylcyclobutyl)-6-pyrimidin-5-yl-1,3-benzothiazole;Cis-{(2S)-1-[3-(6-pyrimidin-5-yl-1,3-benzothiazol-2-yl)cyclobutyl]pyrrolidin-2-yl}methanol;Cis-((2S)-1-{3-[6-(2-methoxypyrimidin-5-yl)-1,3-benzothiazol-2-yl]cyclobutyl}pyrrolidin-2-yl)methanol;Cis-2-{3-[(3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]cyclobutyl}-6-pyrimidin-5-yl-1,3-benzothiazole;Cis-2-{3-[(3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]cyclobutyl}-6-(2-methoxypyrimidin-5-yl)-1,3-benzothiazole;Cis-2-{3-[(2R)-2-methylpiperidin-1-yl]cyclobutyl}-6-pyrimidin-5-yl-1,3-benzothiazole;Cis-N-isopropyl-N-methyl-N-[3-(6-pyrimidin-5-yl-1,3-benzothiazol-2-yl)cyclobutyl]amine;Cis-{1-[3-(6-pyrimidin-5-yl-1,3-benzothiazol-2-yl)cyclobutyl]piperidin-4-yl}methanol;Trans-{1-[3-(6-pyrimidin-5-yl-1,3-benzothiazol-2-yl)cyclobutyl]piperidin-4-yl}methanol;Trans-2-(3-piperidin-1-ylcyclobutyl)-6-pyrimidin-5-yl-1,3-benzothiazole;Trans-6-(2,6-dimethylpyridin-3-yl)-2-(3-piperidin-1-ylcyclobutyl)-1,3-benzothiazole;Trans-6-(6-methoxypyridin-3-yl)-2-(3-piperidin-1-ylcyclobutyl)-1,3-benzothiazole;Trans-6-(2-methoxypyrimidin-5-yl)-2-(3-piperidin-1-ylcyclobutyl)-1,3-benzothiazole;Trans-2-[2-(3-piperidin-1-ylcyclobutyl)-1,3-benzothiazol-6-yl]pyridazin-3(2H)-one;Cis-2-[2-(3-piperidin-1-ylcyclobutyl)-1,3-benzothiazol-6-yl]pyridazin-3(2H)-one;Trans-6-methyl-2-[2-(3-piperidin-1-ylcyclobutyl)-1,3-benzothiazol-6-yl]pyridazin-3(2H)-one;Trans-3-methyl-1-[2-(3-piperidin-1-ylcyclobutyl)-1,3-benzothiazol-6-yl]pyridin-2(1H)-one;Trans-6-(1-methyl-1H-pyrazol-4-yl)-2-(3-piperidin-1-ylcyclobutyl)-1,3-benzothiazole;Trans-N-isopropyl-N-methyl-N-[3-(6-pyrimidin-5-yl-1,3-benzothiazol-2-yl)cyclobutyl]amine;Trans-N-isopropyl-N-{3-[6-(2-methoxypyrimidin-5-yl)-1,3-benzothiazol-2-yl]cyclobutyl}-N-methylamine;Trans-N-isopropyl-N-{3-[6-6-methoxypyridin-3-yl)-1,3-benzothiazol-2-yl]cyclobutyl}-N-methylamine;Trans-N-isopropyl-N-{3-[6-(2-methoxypyridin-3-yl)-1,3-benzothiazol-2-yl]cyclobutyl}-N-methylamine;Trans-N-{3-[6-(2,6-dimethylpyridin-3-yl)-1,3-benzothiazol-2-yl]cyclobutyl}-N-isopropyl-N-methylamine;Trans-2-(2-{3-[isopropyl(methyl)amino]cyclobutyl}-1,3-benzothiazol-6-yl)pyridazin-3(2H)-one;Trans-2-(2-{3-[isopropyl(methyl)amino]cyclobutyl}-1,3-benzothiazol-6-yl)-6-methylpyridazin-3(2H)-one;Trans-1-(2-{3-[isopropyl(methyl)amino]cyclobutyl}-1,3-benzothiazol-6-yl)-3-methylpyridin-2(1H)-one;Trans-1-(2-{3-[isopropyl(methyl)amino]cyclobutyl}-1,3-benzothiazol-6-yl)-5-methylpyridin-2(1H)-one;Trans-2-(3-azetidin-1-ylcyclobutyl)-6-pyrimidin-5-yl-1,3-benzothiazole;Trans-6-pyrimidin-5-yl-2-(3-pyrrolidin-1-ylcyclobutyl)-1,3-benzothiazole;Trans-6-(2,6-dimethylpyridin-3-yl)-2-(3-pyrrolidin-1-ylcyclobutyl)-1,3-benzothiazole;Trans-6-(2-methoxypyrimidin-5-yl)-2-(3-pyrrolidin-1-ylcyclobutyl)-1,3-benzothiazole;Trans-6-(2,4-dimethoxypyrimidin-5-yl)-2-(3-pyrrolidin-1-ylcyclobutyl)-1,3-benzothiazole;Trans-6-(6-methoxypyridin-3-yl)-2-(3-pyrrolidin-1-ylcyclobutyl)-1,3-benzothiazole;Trans-2-[2-(3-pyrrolidin-1-ylcyclobutyl)-1,3-benzothiazol-6-yl]pyridazin-3(2H)-one;Trans-6-methyl-2-[2-(3-pyrrolidin-1-ylcyclobutyl)-1,3-benzothiazol-6-yl]pyridazin-3(2H)-one;Trans-5-methyl-1-[2-(3-pyrrolidin-1-ylcyclobutyl)-1,3-benzothiazol-6-yl]pyridin-2(1H)-one;Trans-3-methyl-1-[2-(3-pyrrolidin-1-ylcyclobutyl)-1,3-benzothiazol-6-yl]pyridin-2(1H)-one;Trans-2-(3-azepan-1-ylcyclobutyl)-6-pyrimidin-5-yl-1,3-benzothiazole;Trans-2-(3-morpholin-4-ylcyclobutyl)-6-pyrimidin-5-yl-1,3-benzothiazole;Trans-2-{3-[(2S)-2-(fluoromethyl)pyrrolidin-1-yl]cyclobutyl}-6-pyrimidin-5-yl-1,3-benzothiazole;Trans-{(2S)-1-[3-(6-pyrimidin-5-yl-1,3-benzothiazol-2-yl)cyclobutyl]pyrrolidin-2-yl}methanol;Trans-((2S)-1-{3-[6-(2,6-dimethylpyridin-3-yl)-1,3-benzothiazol-2-yl]cyclobutyl}pyrrolidin-2-yl)methanol;Trans-2-[3-(2-methylpiperidin-1-yl)cyclobutyl]-6-pyrimidin-5-yl-1,3-benzothiazole;Trans-2-(3-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-ylcyclobutyl)-6-pyrimidin-5-yl-1,3-benzothiazole;Trans-2-[3-(4-fluoropiperidin-1-yl)cyclobutyl]-6-pyrimidin-5-yl-1,3-benzothiazole;Trans-2-[3-(4-fluoropiperidin-1-yl)cyclobutyl]-6-(2-methoxypyrimidin-5-yl)-1,3-benzothiazole;Trans-6-(2,6-dimethylpyridin-3-yl)-2-[3-(4-fluoropiperidin-1-yl)cyclobutyl]-1,3-benzothiazole;Trans-(3R)-1-[3-(6-pyrimidin-5-yl-1,3-benzothiazol-2-yl)cyclobutyl]piperidin-3-ol;Trans-N-ethyl-N-propyl-N-[3-(6-pyrimidin-5-yl-1,3-benzothiazol-2-yl)cyclobutyl]amine;Trans-Diethyl-[3-(6-pyrimidin-5-yl-benzothiazol-2-yl)-cyclobutyl]-amine;Trans-Diethyl-{3-[6-(2-methoxy-pyrimidin-5-yl)-benzothiazol-2-yl]-cyclobutyl}-amine;Trans-{3-[6-(2-Methoxy-pyrimidin-5-yl)-benzothiazol-2-yl]-cyclobutyl}-methyl-propyl-amine;Trans-{3-[6-(2,6-Dimethyl-pyridin-3-yl)-benzothiazol-2-yl]-cyclobutyl}-methyl-propyl-amine;Trans-Methyl-{3-[6-(1-methyl-1H-pyrazol-4-yl)-benzothiazol-2-yl]-cyclobutyl}-propyl-amine;Trans-2-(Ethyl-{3-[6-(2-methoxy-pyrimidin-5-yl)-benzothiazol-2-yl]-cyclobutyl}-amino)-ethanol;Trans-2-({3-[6-(2,6-Dimethyl-pyridin-3-yl)-benzothiazol-2-yl]-cyclobutyl}-ethyl-amino)-ethanol;6-Pyrimidin-5-yl-2-(3-pyrrolidin-1-ylmethyl-cyclobutyl)-benzothiazole;Trans-5-(2,6-Dimethyl-pyridin-3-yl)-2-[3-(2-methyl-pyrrolidin-1-yl)-cyclobutyl]-benzothiazole;Trans-5-(2,4-Dimethoxy-pyrimidin-5-yl)-2-[3-(2-methyl-pyrrolidin-1-yl)-cyclobutyl]-benzothiazole;Trans-6-(1-Methyl-1H-pyrazol-4-yl)-2-[3-(2-methyl-pyrrolidin-1-yl)-cyclobutyl]-benzothiazole;Trans-2-[3-(4-Fluoro-piperidin-1-yl)-cyclobutyl]-6-(1-methyl-1H-pyrazol-4-yl)-benzothiazole;Trans-2-(3-azetidin-1-ylcyclobutyl)-6-(2-methoxypyrimidin-5-yl)-1,3-benzothiazole;Trans-2-(3-azetidin-1-ylcyclobutyl)-6-(2,6-dimethylpyridin-3-yl)-1,3-benzothiazole;Trans-2-(3-azetidin-1-ylcyclobutyl)-6-(1-methyl-1H-pyrazol-4-yl)-1,3-benzothiazole;Trans-2-(3-azepan-1-ylcyclobutyl)-6-(2-methoxypyrimidin-5-yl)-1,3-benzothiazole;Trans-2-(3-azepan-1-ylcyclobutyl)-6-(2,6-dimethylpyridin-3-yl)-1,3-benzothiazole;Trans-2-(3-azepan-1-ylcyclobutyl)-6-(1-methyl-1H-pyrazol-4-yl)-1,3-benzothiazole;Cis-N-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-acetamide;Cis-2-Chloro-N-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-acetamide;Cis-N-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-propionamide;Cis-N-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-isobutyramide;Cis-Cyclopropanecarboxylicacid[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-amide;Cis-Cyclobutanecarboxylicacid[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-amide;Cis-Cyclopentanecarboxylicacid[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-amide;Cis-Cyclohexanecarboxylicacid[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-amide;Cis-Furan-2-carboxylicacid[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-amide;Cis-4-Cyano-N-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-benzamide;Cis-4-Cyano-N-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-benzenesulfonamide;Cis-Thiophene-2-sulfonicacid-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-amide;Cis-Thiophene-2-carboxylicacid-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-amide;Cis-Thiophene-2-carboxylicacid-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-amide;Cis-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-carbamic acidisobutyl ester; Cis-Morpholine-4-carboxylicacid-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-amide;Cis-Pyrazine-2-carboxylicacid-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-amide;Cis-N-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-2-thiophen-3-yl-acetamide;Cis-N-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-3-thiophen-2-yl-propionamide;Cis-3-Furan-2-yl-N-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-propionamide;Cis-Pyrimidine-5-carboxylicacid-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-amide;Trans-4-Cyano-N-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-benzamide;Trans-N-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-propionamide;Trans-N-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-isobutyramide;Trans-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-carbamic acidisobutyl ester; Trans-Cyclopropanecarboxylicacid[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-amide;Trans-Cyclobutanecarboxylicacid[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-amide;Trans-Cyclopentanecarboxylicacid[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-amide;Trans-Cyclohexanecarboxylicacid[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-amide; Trans-Furan-2-carboxylicacid[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-amide;Trans-Morpholine-4-carboxylicacid-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-amide;Trans-Pyrimidine-5-carboxylicacid-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-amide;Trans-Pyrazine-2-carboxylicacid-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-amide;Racemic-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-pyrimidin-5-yl-amine;Racemic-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-pyrimidin-2-yl-amine;Racemic-(5-bromo-pyrimidin-2-yl)-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-amine;Racemic-(5-methyl-pyridin-2-yl)-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-yl]-amine;Racemic-6-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-ylamino]-nicotinonitrile;Racemic-6-[2-(3-Piperidin-1-yl-cyclobutyl)-benzothiazole-6-ylamino]-nicotinonitrile;2-{Trans-3-[(S)-2-methylpiperidin-1-yl]cyclobutyl}-1,3-benzothiazol-6-yl-azetidin-2-one;2-{Trans-3-[(S)-2-methylpiperidin-1-yl]cyclobutyl}-1,3-benzothiazol-6-yl-pyrrolidin-2-one;2-{Trans-3-[(S)-2-methylpiperidin-1-yl]cyclobutyl}-1,3-benzothiazol-6-yl-piperidin-2-one;2-{Trans-3-[(S)-2-methylpiperidin-1-yl]cyclobutyl}-1,3-benzothiazol-6-yl-homopyrrolidin-2-one;2-{Trans-3-[(S)-2-methylpiperidin-1-yl]cyclobutyl}-1,3-benzothiazole-6-carboxamide;N-Isopropyl-2-{trans-3-[(S)-2-methylpiperidin-1-yl]cyclobutyl}-1,3-benzothiazole-6-carboxamide;N-cyclopropyl-2-{trans-3-[(S)-2-methylpiperidin-1-yl]cyclobutyl}-1,3-benzothiazole-6-carboxamide;N-phenyl-2-{trans-3-[(S)-2-methylpiperidin-1-yl]cyclobutyl}-1,3-benzothiazole-6-carboxamide;N-thiazol-2-yl-2-{trans-3-[(S)-2-methylpiperidin-1-yl]cyclobutyl}-1,3-benzothiazole-6-carboxamide;N-benzyl-2-{trans-3-[(S)-2-methylpiperidin-1-yl]cyclobutyl}-1,3-benzothiazole-6-carboxamide;N-(2-phenethyl)-2-{trans-3-[(S)-2-methylpiperidin-1-yl]cyclobutyl}-1,3-benzothiazole-6-carboxamide;N,N-dimethyl-2-{trans-3-[(S)-2-methylpiperidin-1-yl]cyclobutyl}-1,3-benzothiazole-6-carboxamide;(Pyrrolidin-1-yl)-2-{trans-3-[(S)-2-methylpiperidin-1-yl]cyclobutyl}-1,3-benzothiazole-6-methanone;2-[Trans-3-(piperidin-1-yl)cyclobutyl]-1,3-benzothiazol-6-yl-3-methyl-pyrrolidin-2-one;2-[Trans-3-(piperidin-1-yl)cyclobutyl]-1,3-benzothiazol-6-yl-oxazolidin-2-one;2-[Trans-3-(piperidin-1-yl)cyclobutyl]-1,3-benzothiazol-6-yl-3-methylimidazolidin-2-one;Trans-6-bromo-2-{3-[(2R)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazole;Trans-6-bromo-2-{3-[(2S)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazole;Cis6-bromo-2-{3-[(2R)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazole;Cis-6-bromo-2-(3-pyrrolidin-1-ylcyclobutyl)-1,3-benzothiazole;Cis-6-bromo-2-(3-piperidin-1-ylcyclobutyl)-1,3-benzothiazole;Cis-2-(3-azepan-1-ylcyclobutyl)-6-bromo-1,3-benzothiazole;Cis-{(2S)-1-[3-(6-bromo-1,3-benzothiazol-2-yl)cyclobutyl]pyrrolidin-2-yl}methanol;Cis-tert-butyl(3aR,6aR)-5-[3-(6-bromo-1,3-benzothiazol-2-yl)cyclobutyl]hexahydropyrrolo[3,4-b]pyrrole-1(2H)-carboxylate;Cis-6-bromo-2-{3-[(2R)-2-methylpiperidin-1-yl]cyclobutyl}-1,3-benzothiazole;Cis-N-[3-(6-bromo-1,3-benzothiazol-2-yl)cyclobutyl]-N-isopropyl-N-methylamine;Cis-{1-[3-(6-bromo-1,3-benzothiazol-2-yl)cyclobutyl]piperidin-4-yl}methanol;Trans-{1-[3-(6-bromo-1,3-benzothiazol-2-yl)cyclobutyl]piperidin-4-yl}methanol;Trans-6-bromo-2-(3-piperidin-1-ylcyclobutyl)-1,3-benzothiazole;Trans-N-[3-(6-bromo-1,3-benzothiazol-2-yl)cyclobutyl]-N-isopropyl-N-methylamine;Trans-2-(3-azetidin-1-ylcyclobutyl)-6-bromo-1,3-benzothiazole;Trans-6-bromo-2-(3-pyrrolidin-1-ylcyclobutyl)-1,3-benzothiazole;Trans-2-(3-azepan-1-ylcyclobutyl)-6-bromo-1,3-benzothiazole;Trans-6-bromo-2-(3-morpholin-4-ylcyclobutyl)-1,3-benzothiazole;Trans-6-bromo-2-{3-[(2S)-2-(fluoromethyl)pyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazol;Trans-{(2S)-1-[3-(6-bromo-1,3-benzothiazol-2-yl)cyclobutyl]pyrrolidin-2-yl}methanol;Trans-6-bromo-2-[3-(2-methylpiperidin-1-yl)cyclobutyl]-1,3-benzothiazole;Trans-tert-butyl5-[3-(6-bromo-1,3-benzothiazol-2-yl)cyclobutyl]hexahydropyrrolo[3,4-b]pyrrole-1(2H)-carboxylate;Trans-6-bromo-2-[3-(4-fluoropiperidin-1-yl)cyclobutyl]-1,3-benzothiazole;Trans-[3-(6-Bromo-benzothiazol-2-yl)-cyclobutyl]-diethyl-amine;Trans-[3-(6-Bromo-benzothiazol-2-yl)-cyclobutyl]-methyl-propyl-amine;Trans-2-{[3-(6-Bromo-benzothiazol-2-yl)-cyclobutyl]-ethyl-amino}-ethanol;6-Bromo-2-(3-pyrrolidin-1-ylmethyl-cyclobutyl)-benzothiazole; andTrans-5-Chloro-2-[3-(2-methyl-pyrrolidin-1-yl)-cyclobutyl]-benzothiazole.15. The compound of claim 1, selected from the group consisting of:Trans-2-(3-piperidin-1-ylcyclobutyl)-6-pyrimidin-5-yl-1,3-benzothiazole;Trans-Diethyl-{3-[6-(2-methoxy-pyrimidin-5-yl)-benzothiazol-2-yl]-cyclobutyl}-amine;andTrans-2-(Ethyl-{3-[6-(2-methoxy-pyrimidin-5-yl)-benzothiazol-2-yl]-cyclobutyl}-amino)-ethanol;Trans-2-[2-(3-piperidin-1-ylcyclobutyl)-1,3-benzothiazol-6-yl]pyridazin-3(2H)-one;andCis-2-[2-(3-piperidin-1-ylcyclobutyl)-1,3-benzothiazol-6-yl]pyridazin-3(2H)-one.16. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound of claim 1 in combination with a pharmaceuticallyacceptable carrier.
 17. A compound that istrans-2-[2-(3-piperidin-1-ylcyclobutyl)-1,3-benzothiazol-6-yl]pyridazin-3(2H)-oneor a pharmaceutically acceptable salt thereof.
 18. A compound that iscis-2-[2-(3-piperidin-1-ylcyclobutyl)-1,3-benzothiazol-6-yl]pyridazin-3(2H)-oneor a pharmaceutically acceptable salt thereof.